Cell-binding IgM in CSF is distinctive of multiple sclerosis and targets the iron transporter SCARA5.

Intrathecal IgM production in multiple sclerosis is associated with a worse disease course. To investigate pathogenic relevance of autoreactive IgM in multiple sclerosis, CSF from two independent cohorts, including multiple sclerosis patients and controls, were screened for antibody binding to induced pluripotent stem cell-derived neurons and astrocytes, and a panel of CNS-related cell lines. IgM binding to a primitive neuro-ectodermal tumour cell line discriminated 10% of multiple sclerosis donors from controls. Transcriptomes of single IgM producing CSF B cells from patients with cell-binding IgM were sequenced and used to produce recombinant monoclonal antibodies for characterization and antigen identification. We produced five cell-binding recombinant IgM antibodies, of which one, cloned from an HLA-DR + plasma-like B cell, mediated antigen-dependent complement activation. Immunoprecipitation and mass spectrometry, and biochemical and transcriptome analysis of the target cells identified the iron transport scavenger protein SCARA5 as the antigen target of this antibody. Intrathecal injection of a SCARA5 antibody led to an increased T cell infiltration in an experimental autoimmune encephalomyelitis (EAE) model. CSF IgM might contribute to CNS inflammation in multiple sclerosis by binding to cell surface antigens like SCARA5 and activating complement, or by facilitating immune cell migration into the brain.

The CD36 and SR-A/CD204 scavenger receptors fine-tune Staphylococcus aureus-stimulated cytokine production in mouse macrophages.

The occurring in SR-A/CD204- or CD36-deficient mice increased susceptibility to infections with Staphylococcus aureus (Sa) had traditionally been ascribed to the impairment of macrophage-mediated phagocytosis, which is, however, inconsistent with low effectiveness of unopsonized Sa killing within macrophages and redundant roles of both receptors in this process. We have found that Sa-stimulated cytokine production in mouse macrophages seems to be exclusively mediated by TLR2, mainly from within endosomes in response to Sa-derived lipoteichoic acid. By driving endocytic trafficking of TLR2 and its ligands through the clathrin-dependent pathway, CD36 and SR-A sensitize macrophages to activation by Sa as well as regulate the type and amount of cytokines produced. Additionally, upon direct Sa binding, both receptors autonomously generate anti-inflammatory signaling. Consequently, the delayed induction of acute inflammation in knockout mice may allow for the initial, uncontrolled multiplication of bacteria, stimulating excessive, septic shock-inducing production of inflammatory cytokines in later stages of infection.

Role of macrophage scavenger receptor MSR1 in the progression of non-alcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD), and the dysregulation of lipid metabolism and oxidative stress are the typical features. Subsequent dyslipidemia and oxygen radical production may render the formation of modified lipids. Macrophage scavenger receptor 1 (MSR1) is responsible for the uptake of modified lipoprotein and is one of the key molecules in atherosclerosis. However, the unrestricted uptake of modified lipoproteins by MSR1 and the formation of cholesterol-rich foamy macrophages also can be observed in NASH patients and mouse models. In this review, we highlight the dysregulation of lipid metabolism and oxidative stress in NASH, the alteration of MSR1 expression in physiological and pathological conditions, the formation of modified lipoproteins, and the role of MSR1 on macrophage foaming and NASH development and progression.

Infiltration of CD204-overexpressing Macrophages Contributes to the Progression of Stage II and III Colorectal Cancer.

BACKGROUND/AIM: M1 macrophages have antitumour effects, while M2 macrophages promote tumour proliferation and invasion. The clinical significance of the M2-specific marker CD204 has not been elucidated in colorectal cancer (CRC). We investigated the prognostic significance of CD204- and CD68-positivity in specimens from patients with CRC and examined the effects of M2 polarized-macrophages on the proliferative and invasive potentials of CRC cell lines in vitro. MATERIALS AND METHODS: Surgical tumour specimens from 206 patients with Stage II and III CRC were examined by immunohistochemistry. Proliferation and invasion assays and flow cytometry were used to investigate CD204 expression in macrophages co-cultured with three CRC cell lines. RESULTS: Infiltration of CD204-positive cells was significantly associated with shorter overall survival and relapse-free survival; no association was observed for CD68. M2-polarized macrophages significantly promoted proliferation and invasion of CRC cells. CONCLUSION: Higher infiltration of CD204-positive macrophages into the tumour-microenvironment might be prognostically important in CRC.

TAp73 represses NF-κB-mediated recruitment of tumor-associated macrophages in breast cancer.

Infiltration of tumor-promoting immune cells is a strong driver of tumor progression. Especially the accumulation of macrophages in the tumor microenvironment is known to facilitate tumor growth and to correlate with poor prognosis in many tumor types. TAp73, a member of the p53/p63/p73 family, acts as a tumor suppressor and has been shown to suppress tumor angiogenesis. However, what role TAp73 has in regulating immune cell infiltration is unknown. Here, we report that low levels of TAp73 correlate with an increased NF-κB-regulated inflammatory signature in breast cancer. Furthermore, we show that loss of TAp73 results in NF-κB hyperactivation and secretion of Ccl2, a known NF-κB target and chemoattractant for monocytes and macrophages. Importantly, TAp73-deficient tumors display an increased accumulation of protumoral macrophages that express the mannose receptor (CD206) and scavenger receptor A (CD204) compared to controls. The relevance of TAp73 expression in human breast carcinoma was further accentuated by revealing that TAp73 expression correlates negatively with the accumulation of protumoral CD163+ macrophages in breast cancer patient samples. Taken together, our findings suggest that TAp73 regulates macrophage accumulation and phenotype in breast cancer through inhibition of the NF-κB pathway.

CD20+ tumor-infiltrating immune cells and CD204+ M2 macrophages are associated with prognosis in thymic carcinoma.

Thymic carcinoma is a rare malignant disease with no standard systemic chemotherapy. The purpose of the present study was to investigate tumor-infiltrating immune cells (TIIC) in the tumor microenvironment (TME), focusing on the impact of TIIC and program death-ligand 1 (PD-L1) expression on clinical outcomes in thymic cancer. Patients with thymic carcinoma resected between 1973 and 2017 were investigated. The tissue specimens were analyzed through immunohistochemical staining to elucidate the prognostic effects of TIIC, their ratios and PD-L1 in a preliminary cohort (n = 10). The density of TIIC as well as PD-L1 expression was evaluated in intraepithelial and tumor-stromal areas on the representative whole section of tumors. The immune factors showing significant association with disease-free survival (DFS) were evaluated in the total cohort (n = 42). TIIC in the preliminary population showed no significant difference between the two groups. However, CD8, CD20, CD204, FOXP3 and CD20/CD204 ratio demonstrated a tendency to act as predictive markers for recurrence. In the total cohort, significant differences were observed for CD8+ , CD20+ and CD204+ cells in tumor islets, and for CD8+ , CD20+ and FOXP3+ cells as well as the CD8/CD204 and CD20/CD204 ratios in the stroma, indicating their prognostic effect. The prognostic effect of the PD-L1 expression in tumor cells could not be established, possibly because of intratumoral heterogeneity. CD8, CD20 and CD204 positive TIIC in stroma were identified as possible better prognostic biomarkers, considering the heterogeneity of other biomarkers. The present study paves the way for exploring strategies of combination immunotherapy targeting B cell immunity in thymic carcinoma.

Stimulation of the class-A scavenger receptor induces neutrophil extracellular traps (NETs) by ERK dependent NOX2 and ROMO1 activation.

Neutrophil extracellular traps (NETs) play a critical role in host antimicrobial response whereas they are also implicated in the pathogenesis of inflammatory and autoimmunediseases. Generation of reactiveoxygen species (ROS) is key to NETs formation. A variety of stimulatory ligands have been found to enhance ROS production and thus trigger NETs. However, the mechanisms that connect receptor stimuli with ROS production and NETs formation remain unclear. In this study, we described a new mechanism of NETs generation in neutrophils triggered by stimulation of the class A scavenger receptor (SRA), a major subtype of scavenger receptors in response to various stimuli during infection and inflammatory disorders. By using polyinosinic acid (Poly I), a ribonucleotide ligand of SRA, we demonstrated that SRA stimulation lead to selective ERK phosphorylation, which upregulated cytosol ROS levels and induced canonical NETs formation by activating NADPH oxidase 2 (NOX2). Interestingly, our results showed that mitochondrial ROS (mtROS) production was also enhanced by the SRA dependent ERK activation through upregulation and activation of reactive oxygen species modulator 1(ROMO1), a mitochondrial membrane protein and a key mediator of mtROS. Moreover, inhibition of the SRA elicited ROMO1 activation dampened NETs release upon SRA stimulation. Overall, our study describes a new insight into the NETs release triggered by membrane SRA stimulation and mediated by ERK dependent NOX2 and ROMO1 activation.

Macrophages infiltrating endometriosis-like lesions exhibit progressive phenotype changes in a heterologous mouse model.

Endometriotic lesion development involves complex interactions between endometrial tissue, the peritoneum and immune cells. Macrophages are essential in this process; however their precise roles are not defined. To investigate whether infiltrating macrophages acquire functionally different phenotypes during lesion development, human endometrial tissues were grafted into immunodeficient mice expressing macrophage-specific green fluorescent protein (GFP). Although the numbers of GFP-positive macrophages were similar in lesions 4, 7, 10 and 14 days after grafting, their surface markers changed over time. Inflammatory markers MHC class II (MHC II) and iNOS were present on 36% and 41% of macrophages respectively early in lesion development at day 4, whereas abundance of tissue remodelling markers peaked later, with arginase 1 most highly expressed on 57% of macrophages at day 7 and scavenger receptor A (CD204) on 66% of macrophages at day 14. This is consistent with a transition from classical M1 macrophage activity to an alternate M2 profile, which correlates to histological hallmarks of initially acute inflammation followed by tissue remodelling during lesion development. This progressive shift in phenotype is likely to be relevant to the mechanisms by which macrophages are central players in endometriosis-like lesion development.

Extracellular dsRNA induces a type I interferon response mediated via class A scavenger receptors in a novel Chinook salmon derived spleen cell line.

Despite increased global interest in Chinook salmon aquaculture, little is known of their viral immune defenses. This study describes the establishment and characterization of a continuous cell line derived from Chinook salmon spleen, CHSS, and its use in innate immune studies. Optimal growth was seen at 14-18 °C when grown in Leibovitz's L-15 media with 20% fetal bovine serum. DNA analyses confirmed that CHSS was Chinook salmon and genetically different from the only other available Chinook salmon cell line, CHSE-214. Unlike CHSE-214, CHSS could bind extracellular dsRNA, resulting in the rapid and robust expression of antiviral genes. Receptor/ligand blocking assays confirmed that class A scavenger receptors (SR-A) facilitated dsRNA binding and subsequent gene expression. Although both cell lines expressed three SR-A genes: SCARA3, SCARA4, and SCARA5, only CHSS appeared to have functional cell-surface SR-As for dsRNA. Collectively, CHSS is an excellent cell model to study dsRNA-mediated innate immunity in Chinook salmon.

The characterization and initial immune functional analysis of SCARA5 in turbot (Scophthalmus maximus L.).

Scavenger receptors (SRs) are a group of membrane-bound receptors that could bind to a variety of ligands including endogenous proteins and pathogens. SRs have been recognized to play vital roles in innate immune response against pathogen infection in both vertebrates and invertebrates. In this regard, one SmSCARA5 gene was captured in turbot (Scophthalmus maximus). The full-length SmSCARA5 transcript contains an open reading frame (ORF) of 1494 bp. SmSCARA55 showed both the highest identity and similarity to half-smooth tongue sole (Cynoglossus semilaevis), and a high degree of conservation of genomic structure to the teleost species. In addition, the phylogenetic tree analysis showed SmSCARA5 had the closest relationship to half-smooth tongue sole, the syntenic analysis revealed a relatively conserved synteny pattern of SmSCARA5 to other species. Moreover, SmSCARA5 was ubiquitously expressed in all the examined tissues, with the highest expression level in brain and the lowest expression level in blood. And it was significantly down-regulated in intestine following Gram-negative bacteria Vibrio anguillarum, and Gram-positive bacteria Streptococcus iniae challenge. Finally, the recombinant SmSCARA5 showed the highest affinity to lipopolysaccharide (LPS), followed by peptidoglycan (PGN) and lipoteichoic acid (LTA), as well as the strong inhibition effect on the growth of V. anguillarum. Taken together, our results suggested SmSCARA5 plays vital roles in innate immune response in teleost, further studies should be carried out to better understand its regulatory mechanism for innate inflammation response in teleost.

Scavenger receptor-mediated Ad5 entry and acLDL accumulation in monocytes/macrophages synergistically trigger innate responses against viral infection.

Adenovirus serotype 5 (Ad5) is a common cause of respiratory tract infection, and populations worldwide have high prevalence of anti-Ad5 antibodies, implying extensively prior infection. Ad5 infection potently activates the host innate defense and inflammation, but the molecular mechanisms are not completely clarified. We report here that monocytes from Ad5-seropositive subjects upregulates the expression of scavenger receptor A (SR-A), and the increased SR-A promote the susceptibility of Ad5 entry and subsequent innate signaling activation. SR-A is also known as major receptor for lipid uptake, we therefore observed that monocytes from Ad5-seropositive subjects accumulated the acetylated low-density lipoprotein (acLDL) and had the elevated cellular stress to induce the activation of monocyte/macrophages. These findings demonstrate that SR-A-mediated Ad5 entry, innate signaling activation and acLDL accumulation synergistically trigger the robust antiviral innate and inflammatory responses, which are helpful to our understanding of the pathogenesis of adenovirus infection.

Direct binding and internalization of diverse extracellular nucleic acid species through the collagenous domain of class A scavenger receptors.

Nucleic acids are potential pathogen-associated or danger-associated molecular patterns that modulate immune responses and the development of autoimmune disorders. Class A scavenger receptors (SR-As) are a diverse group of pattern recognition receptors that recognize a variety of polyanionic ligands including nucleic acids. While SR-As are important for the recognition and internalization of extracellular dsRNA, little is known about extracellular DNA, despite its association with chronic infections and autoimmune disorders. In this study, we investigated the specificity of and requirement for SR-As in binding and internalizing different species, sequences and lengths of nucleic acids. We purified recombinant coiled-coil/collagenous and scavenger receptor cysteine-rich (SRCR) domains that have been implicated as potential ligand-binding domains. We detected a direct interaction of RNA and DNA species with the coiled-coil/collagenous domain, but not the SRCR domain. Despite the presence of additional surface receptors that bind nucleic acids, SR-As were found to be sufficient for nucleic acid binding and uptake in A549 human lung epithelial cells. Moreover, these findings suggest that the coiled-coil/collagenous domain of SR-As is sufficient to bind nucleic acids independent of species, sequence or length.

Effects of scavenger receptors-1 class A stimulation on macrophage morphology and highly modified advanced glycation end product-protein phagocytosis.

Advanced glycation end-products (AGEs), which comprise non-enzymatically glycosylated proteins, lipids, and nucleic acid amino groups, play an important role in several diseases and aging processes including angiopathy, renal failure, diabetic complications, and neurodegenerative diseases. Among AGE-associated phenotypes, toxic AGEs, glyceraldehyde-derived AGE-2, and glycolaldehyde-derived AGE-3 are involved in the pathogenesis of diabetic complications. In addition, macrophages are reported to remove extracellular AGEs from tissues via scavenger receptors, leading to the progression of atherosclerosis. In the present study, we found that AGE-2 and AGE-3 enhanced their own endocytic uptake by RAW264.7 mouse macrophage-like cells in a concentration-dependent manner. Furthermore, we demonstrated, for the first time, the morphology of phagocytic macrophages and the endocytosis of AGE particles. The toxic AGEs induced the expression of a scavenger receptor, CD204/scavenger receptors-1 class A (SR-A). Notably, an antibody against CD204 significantly prevented toxic AGE uptake. Moreover, an SR-A antagonistic ligand, fucoidan, also attenuated the AGE-2- and AGE-3-evoked uptake in a concentration-dependent manner. These results indicated that SR-A stimulation, at least in part, plays a role in AGE uptake.

Critical regulation of inflammation via class A scavenger receptor.

BACKGROUND: Inflammation is an important cause of COPD. Alveolar macrophages are the major innate immune cells that have an important role in COPD pathology. Class A scavenger receptor (SR-A) is a pattern recognition receptor expressed on macrophages. This study investigates the role of SR-A in COPD progression via regulation of inflammation. PATIENTS AND METHODS: SR-A expression in COPD patients and control subjects (smokers and nonsmokers without COPD) was measured by immunohistochemistry, immunofluorescence, and real-time PCR. The cytokine levels in BAL were measured by enzyme-linked immunosorbent assay. To further prove our hypothesis, we treated RAW264.7 cells that overexpress SR-A with lipopolysaccharides, poly(I:C), cigarette smoke extract, and H1N1 influenza separated from patients for 24 h and examined the levels of inflammatory cytokines. RESULTS: In both groups, COPD and smokers without COPD, SR-A expression level was upregulated in alveolar macrophages. SR-A mRNA level was positively correlated with inflammatory cytokines and negatively correlated with FEV1% predicted in COPD patients. In RAW-SR-A cells, level of inflammatory cytokines was significantly higher when compared with control ones. CONCLUSION: SR-A could increase inflammation stimulated by cigarette smoke extracts, bacteria, and virus, leading to long-term inflammation in COPD, and thus might be used as a new therapeutic target for COPD treatment.

Identification of three class A scavenger receptors from rainbow trout (Oncorhynchus mykiss): SCARA3, SCARA4, and SCARA5.

Class A scavenger receptors (SR-As) are a family of five surface receptors whose functions in mammals are associated with innate immunity; however, their role in fish immunity requires further elucidation. The present study identifies, performs sequence analysis, and constitutive transcript expression analysis for three SR-A family members, SCARA3, SCARA4 and SCARA5, from rainbow trout. This work will provide a basis for future studies on SR-A function and their role in innate immunity in this economically important fish.

αMß2 Is Antiatherogenic in Female but Not Male Mice.

Atherosclerosis is a complex inflammatory process characterized by monocyte recruitment into the arterial wall, their differentiation into macrophages, and lipid accumulation. Because integrin αMß2 (CD11b/CD18) mediates multiple diverse functions of leukocytes, we examined its role in atherogenesis. αM-/-/ApoE-/- and ApoE-/- mice were fed a control or high fat diet for 3 or 16 wk to induce atherogenesis. Unexpectedly, αM deficiency accelerated development of atherosclerosis in female but not in male mice. The size of aortic root lesions was 3-4.5-fold larger in female αM-/-/ApoE-/- than in ApoE-/- mice. Monocyte and macrophage content within the lesions was increased 2.5-fold in female αM-/-/ApoE-/- mice due to enhanced proliferation. αMß2 elimination promoted gender-dependent foam cell formation due to enhanced uptake of cholesterol by αM-/-/ApoE-/- macrophages. This difference was attributed to enhanced expression of lipid uptake receptors, CD36 and scavenger receptor A1 (SR-A1), in female mice. Macrophages from female αM-/-/ApoE-/- mice showed dramatically reduced expression of FoxM1 transcription factor and estrogen receptors (ER) α and ß. As their antagonists inhibited the effect of 17ß-estradiol (E2), E2 decreased CD36, SR-A1, and foam cell formation in ApoE-/- macrophages in an ERα- and ERß-dependent manner. However, female αM-/-/ApoE-/- macrophages failed to respond to E2 and maintained elevated CD36, SR-A1, and lipid accumulation. FoxM1 inhibition in ApoE-/- macrophages reduced ERs and enhanced CD36 and SR-A1 expression, whereas FoxM1 overexpression in αM-/-/ApoE-/- macrophages reversed their proatherogenic phenotype. We demonstrate a new, surprising atheroprotective role of αMß2 in female ApoE-/- mice. αMß2 maintains ER expression in macrophages and E2-dependent inhibition of foam cell formation.

Phenotypical change of tumor-associated macrophages in metastatic lesions of clear cell renal cell carcinoma.

Macrophages are the main immune cells of the tumor microenvironment in clear cell renal cell carcinoma (ccRCC). A high density of CD163+ or CD204+ tumor-associated macrophages (TAMs), rather than the density of total TAMs, is known to be linked to poor clinical outcome. In the present study, we investigated the phenotypical differences between the paired primary and metastatic lesions in ccRCC cases. Using immunostaining, the densities of CD163+ and CD204+ TAMs in metastatic lesions were found to be significantly lower compared to primary lesions, although the total number of TAMs was increased in metastatic lesions. Since CD163 and CD204 are considered to be the markers of an M2/protumor phenotype in macrophages, TAMs in metastatic lesions are suggested to have a greater M1/inflammatory function compared with those from primary lesions. These findings give new insights in regard to the immunological status of metastatic lesions of ccRCC.

Reconstruction of Toll-like receptor 9-mediated responses in HEK-Blue hTLR9 cells by transfection of human macrophage scavenger receptor 1 gene.

We used human Toll-like receptor 9 (hTLR9)-expressing HEK-Blue hTLR9 cells, which release secreted embryonic alkaline phosphatase (SEAP) upon response to CpG DNA, to evaluate the immunological properties of nucleic acid drug candidates. Our preliminary studies showed that phosphodiester CpG DNA hardly induced any SEAP secretion in HEK-Blue hTLR9 cells. In the current study, therefore, we developed HEK-Blue hTLR9 cells transduced with human macrophage scavenger receptor-1 (hMSR1), a cell-surface DNA receptor, and determined whether HEK-Blue hTLR9/hMSR1 cells respond to phosphorothioate (PS) CpG DNA and phosphodiester (PO) CpG DNA. We selected PS CpG2006, a single-stranded PO CpG DNA (ssCpG), and a tetrapod-like structured DNA (tetrapodna) containing ssCpG (tetraCpG) as model TLR9 ligands. Alexa Fluor 488-labeled ligands were used for flow cytometry. Unlike the mock-transfected HEK-Blue hTLR9 cells, the HEK-Blue hTLR9/hMSR1 cells efficiently took up all three CpG DNAs. SEAP release was almost proportional to the uptake. Treatment of HEK-Blue hTLR9/hMSR1 cells with an anti-hMSR1 antibody significantly reduced the uptake of ssCpG and tetraCpG. Collectively, reconstruction of TLR9-mediated responses to CpG DNA in HEK-Blue hTLR9 cells can be used to evaluate the toxicity of nucleic acid drug candidates with diverse physicochemical properties.

MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1.

Damage-associated molecular patterns (DAMPs) trigger sterile inflammation after tissue injury, but the mechanisms underlying the resolution of inflammation remain unclear. In this study, we demonstrate that common DAMPs, such as high-mobility-group box 1 (HMGB1), peroxiredoxins (PRXs), and S100A8 and S100A9, were internalized through the class A scavenger receptors MSR1 and MARCO in vitro. In ischemic murine brain, DAMP internalization was largely mediated by MSR1. An elevation of MSR1 levels in infiltrating myeloid cells observed 3 d after experimental stroke was dependent on the transcription factor Mafb. Combined deficiency for Msr1 and Marco, or for Mafb alone, in infiltrating myeloid cells caused impaired clearance of DAMPs, more severe inflammation, and exacerbated neuronal injury in a murine model of ischemic stroke. The retinoic acid receptor (RAR) agonist Am80 increased the expression of Mafb, thereby enhancing MSR1 expression. Am80 exhibited therapeutic efficacy when administered, even at 24 h after the onset of experimental stroke. Our findings uncover cellular mechanisms contributing to DAMP clearance in resolution of the sterile inflammation triggered by tissue injury.

Malondialdehyde-acetaldehyde (MAA) adducted surfactant protein induced lung inflammation is mediated through scavenger receptor a (SR-A1).

BACKGROUND: Co-exposure to cigarette smoke and alcohol leads to the generation of high concentrations of acetaldehyde and malondialdehyde in the lung. These aldehydes being highly electrophilic in nature react with biologically relevant proteins such as surfactant protein D (SPD) through a Schiff base reaction to generate SPD adducted malondialdehyde-acetaldehyde adduct (SPD-MAA) in mouse lung. SPD-MAA results in an increase in lung pro-inflammatory chemokine, keratinocyte chemoattractant (KC), and the recruitment of lung lavage neutrophils. Previous in vitro studies in bronchial epithelial cells and macrophages show that scavenger receptor A (SR-A1/CD204) is a major receptor for SPD-MAA. No studies have yet examined the in vivo role of SR-A1 in MAA-mediated lung inflammation. Therefore, we hypothesize that in the absence of SR-A1, MAA-induced inflammation in the lung is reduced or diminished. METHODS: To test this hypothesis, C57BL/6 WT and SR-A1 KO mice were nasally instilled with 50 µg/mL of SPD-MAA for 3 weeks (wks). After 3 weeks, bronchoalveolar lavage (BAL) fluid was collected and assayed for a total cell count, a differential cell count and CXCL1 (KC) chemokine. Lung tissue sections were stained with hematoxylin and eosin (H&E) and antibodies to MAA adduct. RESULTS: Results showed that BAL cellularity and influx of neutrophils were decreased in SR-A1 KO mice as compared to WT following repetitive SPD-MAA exposure. MAA adduct staining in the lung epithelium was decreased in SR-A1 KO mice. In comparison to WT, no increase in CXCL1 was observed in BAL fluid from SR-A1 KO mice over time. CONCLUSIONS: Overall, the data demonstrate that SR-A1/CD204 plays an important role in SPD-MAA induced inflammation in lung.