Interleukin 1α and the inflammatory process.

Inflammation occurs after disruption of tissue homeostasis by cell stress, injury or infection and ultimately involves the recruitment and retention of cells of hematopoietic origin, which arrive at the affected sites to resolve damage and initiate repair. Interleukin 1α (IL-1α) and IL-1ß are equally potent inflammatory cytokines that activate the inflammatory process, and their deregulated signaling causes devastating diseases manifested by severe acute or chronic inflammation. Although much attention has been given to understanding the biogenesis of IL-1ß, the biogenesis of IL-1α and its distinctive role in the inflammatory process remain poorly defined. In this review we examine key aspects of IL-1α biology and regulation and discuss its emerging importance in the initiation and maintenance of inflammation that underlie the pathology of many human diseases.

Molecular hydrogen suppresses Porphyromonas gingivalis lipopolysaccharide-induced increases in interleukin-1 alpha and interleukin-6 secretion in human gingival cells.

Periodontitis is defined as a multifactorial polymicrobial infection accompanied by inflammatory reactions. Porphyromonas gingivalis (Pg) is known as a major pathogen in the initiation and progression of periodontitis, and a major virulence factor is Pg lipopolysaccharide (LPS). Molecular hydrogen (H2) has been reported to act as a gaseous antioxidant, which suppresses periodontitis progression by decreasing gingival oxidative stress. However, no human periodontitis model has examined the anti-inflammatory effects of H2. In this study, we examined the effects of H2 on Pg LPS-induced secretion of 8 types of inflammation markers in a human periodontitis model using human gingival cells with enzyme-linked immunosorbent assays. Our results demonstrated that Pg LPS increased interleukin (IL) 1 alpha (IL-1α) and IL-6 secretion, but H2 significantly suppressed the secretion of both cytokines without cytotoxicity. H2 can suppress the production of IL-1α and IL-6, which are identified as cytokines involved in inflammatory reactions in periodontal disease. Thus, H2 may provide therapeutic applications for periodontitis.

Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1.

Through their capacity to sense danger signals and to generate active interleukin-1ß (IL-1ß), inflammasomes occupy a central role in the inflammatory response. In contrast to IL-1ß, little is known about how IL-1α is regulated. We found that all inflammasome activators also induced the secretion of IL-1α, leading to the cosecretion of both IL-1 cytokines. Depending on the type of inflammasome activator, release of IL-1α was inflammasome dependent or independent. Calcium influx induced by the opening of cation channels was sufficient for the inflammasome-independent IL-1α secretion. In both cases, IL-1α was released primarily in a processed form, resulting from intracellular cleavage by calpain-like proteases. Inflammasome-caspase-1-dependent release of IL-1α and IL-1ß was independent of caspase-1 catalytic activity, defining a mode of action for caspase-1. Because inflammasomes contribute to the pathology of numerous chronic inflammatory diseases such as gout and diabetes, IL-1α antagonists may be beneficial in the treatment of these disorders.

Innate and adaptive interferons suppress IL-1α and IL-1ß production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection.

Interleukin-1 (IL-1) receptor signaling is necessary for control of Mycobacterium tuberculosis (Mtb) infection, yet the role of its two ligands, IL-1α and IL-1ß, and their regulation in vivo are poorly understood. Here, we showed that both IL-1α and IL-1ß are critically required for host resistance and identified two multifunctional inflammatory monocyte-macrophage and DC populations that coexpressed both IL-1 species at the single-cell level in lungs of Mtb-infected mice. Moreover, we demonstrated that interferons (IFNs) played important roles in regulating IL-1 production by these cells in vivo. Type I interferons inhibited IL-1 production by both subsets whereas CD4(+) T cell-derived IFN-γ selectively suppressed monocyte-macrophages. These data provide a cellular basis for both the anti-inflammatory effects of IFNs and probacterial functions of type I IFNs during Mtb infection and reveal differential regulation of IL-1 production by distinct cell populations as an additional layer of complexity in the activity of IL-1 in vivo.

Serum exosomes of chronic gastritis patients infected with Helicobacter pylori mediate IL-1α expression via IL-6 trans-signalling in gastric epithelial cells.

Emerging evidence has linked the exosomes to many immunological disorders, including infectious diseases. However, knowledge regarding the role of exosomes in Helicobacter pylori infection is limited. Here, we show that serum exosomes from chronic gastritis patients with H. pylori infection (Hp exosomes) stimulate the expression of the soluble interleukin (IL)-6 receptor (sIL-6R), which is involved in IL-6 trans-signalling in gastric epithelial cells. Interestingly, sIL-6R up-regulates expression of the proinflammatory cytokine IL-1α, and the neutralization of sIL-6R suppresses IL-1α secretion. Thus, Hp exosomes regulate IL-1α expression via sIL-6R-mediated IL-6 trans-signaling. Altogether, this study reveals a novel perspective in which exosomes play a vital role in immunological mechanisms during H. pylori infection.

Link protein N-terminal peptide and fullerol promote matrix production and decrease degradation enzymes in rabbit annulus cells.

PURPOSE: Intervertebral disc degeneration is a major cause of back pain. Novel therapies for prevention or reversal of disc degeneration are needed. It is desirable for potential therapies to target both inflammation and matrix degeneration. MATERIALS AND METHODS: The combined regenerative potential of link protein N-terminal peptide (LN) and fullerol on annulus fibrosus (AF) cells was evaluated in a 3D culture model. RESULTS: Interleukin-1α (IL-1α)-induced AF cell degeneration was counteracted by fullerol, LN, and fullerol + LN, with the latter having the greatest effect on matrix production as evaluated by real-time polymerase chain reaction and glycosaminoglycan assay. IL-1α-induced increases in pro-inflammatory mediators (interleukin-6 and cyclooxygenase-2) and matrix metalloproteinases (MMP-1, -2, -9, and -13) were also counteracted by fullerol and LN. CONCLUSION: Our data demonstrate that LN and fullerol individually, and in combination, promote matrix production and have anti-inflammatory and anti-catabolic effects on AF cells.

Effects of blue light on inflammation and skin barrier recovery following acute perturbation. Pilot study results in healthy human subjects.

BACKGROUND/PURPOSE: While growing evidence supports the therapeutic effect of 453 nm blue light in chronic inflammatory skin diseases, data on its effects on acutely perturbed human skin are scarce. In this study, we investigated the impact of 453 nm narrow-band LED light on healthy skin following acute perturbation. METHODS: Tape stripping and histamine iontophoresis were performed on the forearm of 22 healthy volunteers on 2 consecutive weeks. In 1 week, challenges were followed by irradiation for 30 minutes. In the other week (control), no light was administered. Reactions were evaluated up to 72 hours thereafter by transepidermal water loss (TEWL), diffuse reflectance spectroscopy, and skin surface biomarkers. RESULTS: Skin barrier disruption resulted in upregulation of IL-1α at 24 hours after tape stripping (P = .029). In contrast, irradiation abrogated this effect (P > .05). Irradiation also resulted in higher TEWL at 24 hours and in higher b* value at 72 hours after tape stripping compared to the control (P = .034 and P = .018, respectively). At 30 minutes following histamine iontophoresis and irradiation, a trend toward a higher a* value compared to the control was observed (P = .051). CONCLUSION: We provide the first in vivo evidence that blue light at 453 nm exerts biological effects on acutely perturbed healthy human skin.

IL-1α Gene Deletion Protects Oligodendrocytes after Spinal Cord Injury through Upregulation of the Survival Factor Tox3.

Spinal cord injury (SCI) causes the release of danger signals by stressed and dying cells, a process that leads to neuroinflammation. Evidence suggests that inflammation plays a role in both the damage and repair of injured neural tissue. We show that microglia at sites of SCI rapidly express the alarmin interleukin (IL)-1α, and that infiltrating neutrophils and macrophages subsequently produce IL-1ß. Infiltration of these cells is dramatically reduced in both IL-1α(-/-) and IL-1ß(-/-) mice, but only IL-1α(-/-) mice showed rapid (at day 1) and persistent improvements in locomotion associated with reduced lesion volume. Similarly, intrathecal administration of the IL-1 receptor antagonist anakinra restored locomotor function post-SCI. Transcriptome analysis of SCI tissue at day 1 identified the survival factor Tox3 as being differentially regulated exclusively in IL-1α(-/-) mice compared with IL-1ß(-/-) and wild-type mice. Accordingly, IL-1α(-/-) mice have markedly increased Tox3 levels in their oligodendrocytes, beginning at postnatal day 10 (P10) and persisting through adulthood. At P10, the spinal cord of IL-1α(-/-) mice showed a transient increase in mature oligodendrocyte numbers, coinciding with increased IL-1α expression in wild-type animals. In adult mice, IL-1α deletion is accompanied by increased oligodendrocyte survival after SCI. TOX3 overexpression in human oligodendrocytes reduced cellular death under conditions mimicking SCI. These results suggest that IL-1α-mediated Tox3 suppression during the early phase of CNS insult plays a crucial role in secondary degeneration. SIGNIFICANCE STATEMENT: The mechanisms underlying bystander degeneration of neurons and oligodendrocytes after CNS injury are ill defined. We show that microglia at sites of spinal cord injury (SCI) rapidly produce the danger signal interleukin (IL)-1α, which triggers neuroinflammation and locomotor defects. We uncovered that IL-1α(-/-) mice have markedly increased levels of the survival factor Tox3 in their oligodendrocytes, which correlates with the protection of this cell population, and reduced lesion volume, resulting in unprecedented speed, level, and persistence of functional recovery after SCI. Our data suggest that central inhibition of IL-1α or Tox3 overexpression during the acute phase of a CNS insult may be an effective means for preventing the loss of neurological function in SCI, or other acute injuries such as ischemia and traumatic brain injuries.

Senescent Vascular Smooth Muscle Cells Drive Inflammation Through an Interleukin-1α-Dependent Senescence-Associated Secretory Phenotype.

OBJECTIVE: Vascular smooth muscle cells (VSMCs) that become senescent are both present within atherosclerotic plaques and thought to be important to the disease process. However, senescent VSMCs are generally considered to only contribute through inaction, with failure to proliferate resulting in VSMC- and collagen-poor unstable fibrous caps. Whether senescent VSMCs can actively contribute to atherogenic processes, such as inflammation, is unknown. APPROACH AND RESULTS: We find that senescent human VSMCs develop a proinflammatory state known as a senescence-associated secretory phenotype. Senescent human VSMCs release high levels of multiple cytokines and chemokines driven by secreted interleukin-1α acting in an autocrine manner. Consequently, the VSMC senescence-associated secretory phenotype promotes chemotaxis of mononuclear cells in vitro and in vivo. In addition, senescent VSMCs release active matrix metalloproteinase-9, secrete less collagen, upregulate multiple inflammasome components, and prime adjacent endothelial cells and VSMCs to a proadhesive and proinflammatory state. Importantly, maintaining the senescence-associated secretory phenotype places a large metabolic burden on senescent VSMCs, such that they can be selectively killed by inhibiting glucose utilization. CONCLUSIONS: Senescent VSMCs may actively contribute toward the chronic inflammation associated with atherosclerosis through the interleukin-1α-driven senescence-associated secretory phenotype and the priming of adjacent cells to a proatherosclerotic state. These data also suggest that inhibition of this potentially important source of chronic inflammation in atherosclerosis requires blockade of interleukin-1α and not interleukin-1ß.

Immune complexes inhibit IL-1 secretion and inflammasome activation.

IgG immune complexes have been shown to modify immune responses driven by APCs in either a pro- or anti-inflammatory direction depending upon the context of stimulation. However, the ability of immune complexes to modulate the inflammasome-dependent innate immune response is unknown. In this study, we show that IgG immune complexes suppress IL-1α and IL-1ß secretion through inhibition of inflammasome activation. The mechanism by which this inhibition occurs is via immune complex ligation of activating FcγRs, resulting in prevention of both activation and assembly of the inflammasome complex in response to nucleotide-binding domain leucine-rich repeat (NLR) P3, NLRC4, or AIM2 agonists. In vivo, administration of Ag in the form of an immune complex during priming of the immune response inhibited resultant adaptive immune responses in an NLRP3-dependent model of allergic airway disease. Our data reveal an unexpected mechanism regulating CD4(+) T cell differentiation, by which immune complexes suppress inflammasome activation and the generation of IL-1α and IL-1ß from APCs, which are critical for the Ag-driven differentiation of CD4(+) T cells.

Expression of IL-1α and IL-6 is Associated with Progression and Prognosis of Human Cervical Cancer.

BACKGROUND IL-1α and IL-6 are associated with the prognosis of a wide range of cancers, but their value in cervical cancer remains controversial. The aim of this study was to investigate the expression of IL-1α and IL-6 in cervical cancer and their significance in clinical prognosis. MATERIAL AND METHODS The expression of IL-1α and IL-6 in 105 formalin-fixed, paraffin-embedded cervical cancer tissues and adjacent non-tumor tissues was examined by immunohistochemistry. The results were semi-quantitatively scored and analyzed by chi-square test. Patient overall survival (OS) data was collected by follow-up and analyzed by Kaplan-Meier analysis. RESULTS The expression level of both IL-1α and IL-6 in cervical cancer tissue was higher than in adjacent non-tumor tissues (p<0.05). IL-1α expression was shown to be correlated with tumor size, FIGO histology grade, lymph node metastasis, stromal invasion, and tumor differentiation (p<0.05). IL-6 expression was shown to be correlated with tumor size, FIGO histology grade, and tumor differentiation (p<0.05). Patients with positive expression of IL-1α or IL-6 tended to have much shorter survival times than patients with negative expression. In addition, a multivariate Cox regression analysis demonstrated that IL-1α expression and lymph node metastasis were independent predictors of OS in cervical cancer patients. CONCLUSIONS The expression of IL-1α was significantly associated with tumor size, FIGO histology grade, lymph node metastasis, stromal invasion, and tumor differentiation. The expression of IL-6 was significantly associated with tumor size, FIGO histology grade, and tumor differentiation. Positive IL-1α and IL-6 expression was significantly correlated with poor prognosis. They may be considered valuable biomarkers for prognosis and potential therapeutic targets for cervical cancer.

Interleukin-1α deficiency attenuates endoplasmic reticulum stress-induced liver damage and CHOP expression in mice.

BACKGROUND & AIMS: ER stress promotes liver fat accumulation and induction of inflammatory cytokines, which contribute to the development of steatohepatitis. Unresolved ER stress upregulates the pro-apoptotic CHOP. IL-1α is localized to the nucleus in apoptotic cells, but is released when these cells become necrotic and induce sterile inflammation. We investigated whether IL-1α is involved in ER stress-induced apoptosis and steatohepatitis. METHODS: We employed WT and IL-1α-deficient mice to study the role of IL-1α in ER stress-induced steatohepatitis. RESULTS: Liver CHOP mRNA was induced in a time dependent fashion in the atherogenic diet-induced steatohepatitis model, and was twofold lower in IL-1α deficient compared to WT mice. In the ER stress-driven steatohepatitis model, IL-1α deficiency decreased the elevation in serum ALT levels, the number of apoptotic cells (measured as caspase-3-positive hepatocytes), and the expression of IL-1ß, IL-6, TNFα, and CHOP, with no effect on the degree of fatty liver formation. IL-1α was upregulated in ER-stressed-macrophages and the protein was localized to the nucleus. IL-1ß mRNA and CHOP mRNA and protein levels were lower in ER-stressed-macrophages from IL-1α deficient compared to WT mice. ER stress induced the expression of IL-1α and IL-1ß also in mouse primary hepatocytes. Recombinant IL-1α treatment in hepatocytes did not affect CHOP expression but upregulated both IL-1α and IL-1ß mRNA levels. CONCLUSION: We show that IL-1α is upregulated in response to ER stress and IL-1α deficiency reduces ER stress-induced CHOP expression, apoptosis and steatohepatitis. As a dual function cytokine, IL-1α may contribute to the induction of CHOP intracellularly, while IL-1α released from necrotic cells accelerates steatohepatitis via induction of inflammatory cytokines by neighboring cells.

Calpains promote neutrophil recruitment and bacterial clearance in an acute bacterial peritonitis model.

Activation of the innate immune system is critical for clearance of bacterial pathogens to limit systemic infections and host tissue damage. Here, we report a key role for calpain proteases in bacterial clearance in mice with acute peritonitis. Using transgenic mice expressing Cre recombinase primarily in innate immune cells (fes-Cre), we generated conditional capns1 knockout mice. Consistent with capns1 being essential for stability and function of the ubiquitous calpains (calpain-1, calpain-2), peritoneal cells from these mice had reduced levels of calpain-2/capns1, and reduced proteolysis of their substrate selenoprotein K. Using an acute bacterial peritonitis model, we observed impaired bacterial killing within the peritoneum and development of bacteremia in calpain knockout mice. These defects correlated with significant reductions in IL-1α release, neutrophil recruitment, and generation of reactive oxygen species in calpain knockout mice with acute bacterial peritonitis. Peritoneal macrophages from calpain knockout mice infected with enterobacteria ex vivo, were competent in phagocytosis of bacteria, but showed impaired clearance of intracellular bacteria compared with control macrophages. Together, these results implicate calpains as key mediators of effective innate immune responses to acute bacterial infections, to prevent systemic dissemination of bacteria that can lead to sepsis.

Paracrine crosstalk between human hair follicle dermal papilla cells and microvascular endothelial cells.

Human follicle dermal papilla cells (FDPC) are a specialized population of mesenchymal cells located in the skin. They regulate hair follicle (HF) development and growth, and represent a reservoir of multipotent stem cells. Growing evidence supports the hypothesis that HF cycling is associated with vascular remodeling. Follicular keratinocytes release vascular endothelial growth factor (VEGF) that sustains perifollicular angiogenesis leading to an increase of follicle and hair size. Furthermore, several human diseases characterized by hair loss, including Androgenetic Alopecia, exhibit alterations of skin vasculature. However, the molecular mechanisms underlying HF vascularization remain largely unknown. In vitro coculture approaches can be successfully employed to greatly improve our knowledge and shed more light on this issue. Here we used Transwell-based co-cultures to show that FDPC promote survival, proliferation and tubulogenesis of human microvascular endothelial cells (HMVEC) more efficiently than fibroblasts. Accordingly, FDPC enhance the endothelial release of VEGF and IGF-1, two well-known proangiogenic growth factors. Collectively, our data suggest a key role of papilla cells in vascular remodeling of the hair follicle.

IL-17 receptor A signaling is protective in infection-stimulated periapical bone destruction.

IL-17 is a pleiotropic cytokine produced by Th17 T cells that induces a myriad of proinflammatory mediators. However, different models of inflammation report opposite functional roles of IL-17 signal in terms of its effects on bone destruction. In this study we determined the role of IL-17RA signal in bone resorption stimulated by dentoalveolar infections. Infrabony resorptive lesions were induced by surgical pulp exposure and microbial infection of mouse molar teeth. IL-17 was strongly induced in periapical tissues in wild-type (WT) mice by 7 d after the infection but was not expressed in uninfected mice. Dentoalveolar infections of IL-17RA knockout (KO) mice demonstrated significantly increased bone destruction and more abscess formation in the apical area compared with WT mice. Infected IL-17RA KO mice exhibited significantly increased neutrophils and macrophages compared with the WT littermates at day 21, suggesting a failure of transition from acute to chronic inflammation in the IL-17RA KO mice. The expression of IL-1 (both α and ß isoforms) and MIP2 were significantly upregulated in the IL-17RA KO compared with WT mice at day 21 postinfection. The development of periapical lesions in IL-17RA KO mice was significantly attenuated by neutralization of IL-1ß and MIP2. Taken together, these results demonstrate that IL-17RA signal seems to be protective against infection-induced periapical inflammation and bone destruction via suppression of neutrophil and mononuclear inflammation.

Redox control of the senescence regulator interleukin-1α and the secretory phenotype.

Senescent cells accumulate in aged tissue and are causally linked to age-associated tissue degeneration. These non-dividing, metabolically active cells are highly secretory and alter tissue homeostasis, creating an environment conducive to metastatic disease progression. IL-1α is a key senescence-associated (SA) proinflammatory cytokine that acts as a critical upstream regulator of the SA secretory phenotype (SASP). We established that SA shifts in steady-state H2O2 and intracellular Ca(2+) levels caused an increase in IL-1α expression and processing. The increase in intracellular Ca(2+) promoted calpain activation and increased the proteolytic cleavage of IL-1α. Antioxidants and low oxygen tension prevented SA IL-1α expression and restricted expression of SASP components IL-6 and IL-8. Ca(2+) chelation or calpain inhibition prevented SA processing of IL-1α and its ability to induce downstream cytokine expression. Conditioned medium from senescent cells treated with antioxidants or Ca(2+) chelators or cultured in low oxygen markedly reduced the invasive capacity of proximal metastatic cancer cells. In this paracrine fashion, senescent cells promoted invasion by inducing an epithelial-mesenchymal transition, actin reorganization, and cellular polarization of neighboring cancer cells. Collectively, these findings demonstrate how SA alterations in the redox state and Ca(2+) homeostasis modulate the inflammatory phenotype through the regulation of the SASP initiator IL-1α, creating a microenvironment permissive to tumor invasion.

Caspase-11: the driving factor for noncanonical inflammasomes.

Inflammasomes are large multiprotein platforms that mediate the processing of caspase-1, which in turn promotes the maturation and release of IL-1ß and IL-18 in response to microbial and danger signals. While the canonical pathway of inflammasome activation has been known for some time, a novel mechanism of noncanonical inflammasome activation mediated by caspase-11 was more recently identified. This pathway engages caspase-11 to trigger both caspase-1-dependent and -independent production of the inflammatory cytokines IL-1ß, IL-18, and IL-1α, as well as to promote pyroptosis, a form of genetically programmed cell death that is associated with the release of such cytokines. In this review, we gather together studies on both the mechanisms and implications of caspase-11-mediated noncanonical inflammasome activation, and discuss the emerging importance of this pathway in regulating host defense against intracellular bacterial pathogens.

p47(phox) directs murine macrophage cell fate decisions.

Macrophage differentiation and function are pivotal for cell survival from infection and involve the processing of microenvironmental signals that determine macrophage cell fate decisions to establish appropriate inflammatory balance. NADPH oxidase 2 (Nox2)-deficient chronic granulomatous disease (CGD) mice that lack the gp91(phox) (gp91(phox-/-)) catalytic subunit show high mortality rates compared with wild-type mice when challenged by infection with Listeria monocytogenes (Lm), whereas p47(phox)-deficient (p47(phox-/-)) CGD mice show survival rates that are similar to those of wild-type mice. We demonstrate that such survival results from a skewed macrophage differentiation program in p47(phox-/-) mice that favors the production of higher levels of alternatively activated macrophages (AAMacs) compared with levels of either wild-type or gp91(phox-/-) mice. Furthermore, the adoptive transfer of AAMacs from p47(phox-/-) mice can rescue gp91(phox-/-) mice during primary Lm infection. Key features of the protective function provided by p47(phox-/-) AAMacs against Lm infection are enhanced production of IL-1α and killing of Lm. Molecular analysis of this process indicates that p47(phox-/-) macrophages are hyperresponsive to IL-4 and show higher Stat6 phosphorylation levels and signaling coupled to downstream activation of AAMac transcripts in response to IL-4 stimulation. Notably, restoring p47(phox) protein expression levels reverts the p47(phox)-dependent AAMac phenotype. Our results indicate that p47(phox) is a previously unrecognized regulator for IL-4 signaling pathways that are important for macrophage cell fate choice.

Transplantation of mesenchymal stem cells into the skeletal muscle induces cytokine generation.

Mesenchymal stem cells due to the high proliferative potential, capacity of multilineage differentiation became a hope of regenerative medicine. However, the organism's response to the transplantation of MSCs is not fully elucidated. The aim of the present study was to evaluate the acute local tissue response to syngeneic MSCs administration into the muscle. Rat syngeneic MSCs were transplanted into the skeletal muscle and the tissue surrounding the injection site was collected after 24h. Analogous samples from untreated and PBS treated muscles served as controls. The analysis of genes expression using real-time PCR revealed significant up-regulation of proinflammatory cytokines: IL-1α, IL-1ß, IL-6 in MSCs treated muscles in comparison to the PBS group. The evaluation of protein concentration (ELISA) in collected samples showed that injection of MSCs caused significant elevation of IL-1ß. Immunofluorescent assessment of the tissue revealed infiltration of leukocytes and macrophages. Quantitative analysis of the samples immunostained for CD68 and CD43 antigens revealed that the number of phagocytes was significantly higher in MSC treated muscle when compared to the samples from PBS group. To conclude, the administration of mesenchymal stem cells into the muscle in syngeneic model induces the features of acute inflammation that affects cell engraftment.

Chlorella vulgaris treatment ameliorates the suppressive effects of single and repeated stressors on hematopoiesis.

The reports regarding the mutual influence between the central nervous system and the immune system constitute a vast and somewhat controversial body of literature. Stress is known to disturb homeostasis, impairing immunological functions. In this study, we investigated the hematopoietic response of Chlorella vulgaris (CV)-treated mice exposed to single (SST) and repeated stress (RST). We observed a reduction in the numbers of hematopoietic progenitors (HP) in the bone marrow and long-term bone marrow cultures (LTBMC) using flow cytometry and a coinciding decrease in the number of granulocyte-macrophage colonies (CFU-GM) after treatment with both stressors, but SST caused a more profound suppression. We observed a proportional increase in the colony-stimulating activity (CSA) of the serum of animals subjected to SST or RST. In the bone marrow, SST and RST induced a decrease in both mature myeloid and lymphoid populations but did not affect pluripotent hematopoietic progenitors (Lin(-)Sca-1(+)c-kit(+), LSK), and again, a more profound suppression was observed after SST. We further quantified the levels of interleukin-1α (IL-1α) and interleukin-6 (IL-6) and the number of myeloid cells in LTBMC. Both SST and RST reduced the levels of these cytokines to similar degrees. The myeloid population was also reduced in LTBMC, and SST induced a more intense suppression. Importantly, CV treatment prevented the changes produced by SST and RST in all of the parameters evaluated. Together, our results suggest that CV treatment is an effective tool for the prophylaxis of myelosuppression caused by single or repeated stressors.