Strategies to engage family physicians in primary care research: A systematic review.

RATIONALE: Moving towards high quality primary health care, involving family physicians in primary care research becomes an essential prerequisite to ensures a better adoption and routinization of patient-centred, evidence-based practices. AIM: To assess the effectiveness of strategies to engage family physicians in primary care research. METHODS: We systematically reviewed evidence for strategies used to engage family physicians in primary care research. We included any study design that reported at least one quantitative outcome. Searches were carried out on MEDLINE, Embase, PsycINFO and Web of Science. Pairs of reviewers independently screened for publications in two stages using standardized forms. We performed data analysis through a narrative synthesis approach, using the Reasoned-action approach as framework. RESULTS: A total of 4859 deduped records were identified of which 41 studies met the eligibility criteria and were included for analysis. The majority of studies (n = 35) investigated family physician's participation in a research project. They aimed to influence family physicians' intention (n = 7) or their ability (n = 3) to participate in a research project. Three types of strategies (compensation/incentive, recruitment by a peer and support from a research network or an academic institution) demonstrated a significant increase in participation rate. Methodological quality of the studies evaluating these strategies was relatively low. Few studies (n = 6) targeted research capacity-building programmes with no significant impact noted. CONCLUSION: Numerous strategies have been used to engage family physicians in primary care research, but few studies evaluated their effectiveness in a rigorous way. REGISTRATION: The protocol of this review was registered with the SPOR Evidence Alliance and on the PROSPERO platform (registration number: CRD42020189322).

The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury.

Spinal cord injury (SCI) triggers neuroinflammation, and subsequently secondary degeneration and oligodendrocyte (OL) death. We report that the alarmin interleukin (IL)-1α is produced by damaged microglia after SCI. Intra-cisterna magna injection of IL-1α in mice rapidly induces neutrophil infiltration and OL death throughout the spinal cord, mimicking the injury cascade seen in SCI sites. These effects are abolished through co-treatment with the IL-1R1 antagonist anakinra, as well as in IL-1R1-knockout mice which demonstrate enhanced locomotor recovery after SCI. Conditional restoration of IL-1R1 expression in astrocytes or endothelial cells (ECs), but not in OLs or microglia, restores IL-1α-induced effects, while astrocyte- or EC-specific Il1r1 deletion reduces OL loss. Conditioned medium derived from IL-1α-stimulated astrocytes results in toxicity for OLs; further, IL-1α-stimulated astrocytes generate reactive oxygen species (ROS), and blocking ROS production in IL-1α-treated or SCI mice prevented OL loss. Thus, after SCI, microglia release IL-1α, inducing astrocyte- and EC-mediated OL degeneration.

FcγRIIA expression accelerates nephritis and increases platelet activation in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by deposits of immune complexes (ICs) in organs and tissues. The expression of FcγRIIA by human platelets, which is their unique receptor for immunoglobulin G antibodies, positions them to ideally respond to circulating ICs. Whereas chronic platelet activation and thrombosis are well-recognized features of human SLE, the exact mechanisms underlying platelet activation in SLE remain unknown. Here, we evaluated the involvement of FcγRIIA in the course of SLE and platelet activation. In patients with SLE, levels of ICs are associated with platelet activation. Because FcγRIIA is absent in mice, and murine platelets do not respond to ICs in any existing mouse model of SLE, we introduced the FcγRIIA (FCGR2A) transgene into the NZB/NZWF1 mouse model of SLE. In mice, FcγRIIA expression by bone marrow cells severely aggravated lupus nephritis and accelerated death. Lupus onset initiated major changes to the platelet transcriptome, both in FcγRIIA-expressing and nonexpressing mice, but enrichment for type I interferon response gene changes was specifically observed in the FcγRIIA mice. Moreover, circulating platelets were degranulated and were found to interact with neutrophils in FcγRIIA-expressing lupus mice. FcγRIIA expression in lupus mice also led to thrombosis in lungs and kidneys. The model recapitulates hallmarks of human SLE and can be used to identify contributions of different cellular lineages in the manifestations of SLE. The study further reveals a role for FcγRIIA in nephritis and in platelet activation in SLE.

Neuronal interleukin-1 receptors mediate pain in chronic inflammatory diseases.

Chronic pain is a major comorbidity of chronic inflammatory diseases. Here, we report that the cytokine IL-1ß, which is abundantly produced during multiple sclerosis (MS), arthritis (RA), and osteoarthritis (OA) both in humans and in animal models, drives pain associated with these diseases. We found that the type 1 IL-1 receptor (IL-1R1) is highly expressed in the mouse and human by a subpopulation of TRPV1+ dorsal root ganglion neurons specialized in detecting painful stimuli, termed nociceptors. Strikingly, deletion of the Il1r1 gene specifically in TRPV1+ nociceptors prevented the development of mechanical allodynia without affecting clinical signs and disease progression in mice with experimental autoimmune encephalomyelitis and K/BxN serum transfer-induced RA. Conditional restoration of IL-1R1 expression in nociceptors of IL-1R1-knockout mice induced pain behavior but did not affect joint damage in monosodium iodoacetate-induced OA. Collectively, these data reveal that neuronal IL-1R1 signaling mediates pain, uncovering the potential benefit of anti-IL-1 therapies for pain management in patients with chronic inflammatory diseases.

Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury.

The role of microglia in spinal cord injury (SCI) remains poorly understood and is often confused with the response of macrophages. Here, we use specific transgenic mouse lines and depleting agents to understand the response of microglia after SCI. We find that microglia are highly dynamic and proliferate extensively during the first two weeks, accumulating around the lesion. There, activated microglia position themselves at the interface between infiltrating leukocytes and astrocytes, which proliferate and form a scar in response to microglia-derived factors, such as IGF-1. Depletion of microglia after SCI causes disruption of glial scar formation, enhances parenchymal immune infiltrates, reduces neuronal and oligodendrocyte survival, and impairs locomotor recovery. Conversely, increased microglial proliferation, induced by local M-CSF delivery, reduces lesion size and enhances functional recovery. Altogether, our results identify microglia as a key cellular component of the scar that develops after SCI to protect neural tissue.

Endogenous T Cell Receptor Rearrangement Represses Aggressive Central Nervous System Autoimmunity in a TcR-Transgenic Model on the Non-Obese Diabetic Background.

The T cell response to central nervous system (CNS) antigen in experimental autoimmune encephalomyelitis (EAE) permits one to model the immune aspects of multiple sclerosis. 1C6 transgenic mice on the non-obese diabetic (NOD) background possess a class II-restricted T cell receptor (TcR; Vα5-Vß7) specific for the encephalitogenic peptide myelin oligodendrocyte glycoprotein (MOG)[35-55]. It remains to be determined what role is played by allelic inclusion in shaping the TcR repertoire of these mice. Here, we show that 1C6 T cells display substantial promiscuity in their expression of non-transgenically derived Vα chains. Further, enforced expression of the transgenic TcR in 1C6 × Rag1-/- mice profoundly disrupted thymic negative selection and led to a sharp decrease in the number of mature peripheral T cells. 1C6 × Rag1-/- mice developed spontaneous EAE at a significant frequency and rapidly developed fatal EAE upon immunization with myelin oligodendrocyte glycoprotein (MOG)[35-55]. Passive transfer of 1C6 × Rag1+/+ CD4+ T cells, but not CD8+ T cells or B cells, partially rescued 1C6 × Rag1-/- mice from severe EAE. FoxP3+ CD4+ Treg cells were present in the CNS of immunized 1C6 mice, as well as immunized 1C6 × Rag1-/- that had been supplemented with 1C6 CD4+ T cells. However, they were not observed in 1C6 × Rag1-/- that did not receive Rag1-sufficient 1C6 CD4+. Further, in vivo blockade of Treg accelerated the onset of symptoms in 1C6 mice immunized with MOG[35-55], indicating the pertinence of Treg-mediated control of autoimmune inflammation in this model. Thus, TcR allelic inclusion is crucial to the generation of FoxP3+ CD4+ T cells necessary for the suppression of severe CNS autoimmunity.

Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration.

There is a growing appreciation for the contribution of platelets to immunity; however, our knowledge mostly relies on platelet functions associated with vascular injury and the prevention of bleeding. Circulating immune complexes (ICs) contribute to both chronic and acute inflammation in a multitude of clinical conditions. Herein, we scrutinized platelet responses to systemic ICs in the absence of tissue and endothelial wall injury. Platelet activation by circulating ICs through a mechanism requiring expression of platelet Fcγ receptor IIA resulted in the induction of systemic shock. IC-driven shock was dependent on release of serotonin from platelet-dense granules secondary to platelet outside-in signaling by αIIbß3 and its ligand fibrinogen. While activated platelets sequestered in the lungs and leaky vasculature of the blood-brain barrier, platelets also sequestered in the absence of shock in mice lacking peripheral serotonin. Unexpectedly, platelets returned to the blood circulation with emptied granules and were thereby ineffective at promoting subsequent systemic shock, although they still underwent sequestration. We propose that in response to circulating ICs, platelets are a crucial mediator of the inflammatory response highly relevant to sepsis, viremia, and anaphylaxis. In addition, platelets recirculate after degranulation and sequestration, demonstrating that in adaptive immunity implicating antibody responses, activated platelets are longer lived than anticipated and may explain platelet count fluctuations in IC-driven diseases.

IL-1ß enables CNS access to CCR2hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells.

Molecular interventions that limit pathogenic CNS inflammation are used to treat autoimmune conditions such as multiple sclerosis (MS). Remarkably, IL-1ß-knockout mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we show that interfering with the IL-1ß/IL-1R1 axis severely impairs the transmigration of myeloid cells across central nervous system (CNS) endothelial cells (ECs). Notably, we report that IL-1ß expression by inflammatory CCR2hi monocytes favors their entry into the spinal cord before EAE onset. Following activation with IL-1ß, CNS ECs release GM-CSF, which in turn converts monocytes into antigen-presenting cells (APCs). Accordingly, spinal cord-infiltrated monocyte-derived APCs are associated with dividing CD4+ T cells. Factors released from the interaction between IL-1ß-competent myeloid cells and CD4+ T cells are highly toxic to neurons. Together, our results suggest that IL-1ß signaling is an entry point for targeting both the initiation and exacerbation of neuroinflammation.

Involvement of the IL-1 system in experimental autoimmune encephalomyelitis and multiple sclerosis: Breaking the vicious cycle between IL-1ß and GM-CSF.

Multiple sclerosis (MS) is an autoimmune disease that affects hundreds of thousands of people worldwide. Given the autoimmune nature of the disease, a large part of the research has focused on autoreactive T and B cells. However, research on the involvement of myeloid cells in the pathophysiology of MS has received a strong and renewed attention over the recent years. Despite the multitude of inflammatory mediators involved in innate immunity, only a select group of cytokines are absolutely critical to the development of CNS autoimmunity, among which is interleukin (IL)-1. While the importance of the IL-1 system in experimental autoimmune encephalomyelitis (EAE) and MS has been recognized for about 20years, it is only recently that we have begun to understand that IL-1 plays multifaceted roles in disease initiation, development, amplification and chronicity. Here, we review the recent findings showing an implication of the IL-1 system in EAE and MS, and introduce a model that highlights how IL-1ß and granulocyte-macrophage colony-stimulating factor (GM-CSF) are interacting together to create a vicious feedback cycle of CNS inflammation that ultimately leads to myelin and neuronal damage.

Myeloid cell transmigration across the CNS vasculature triggers IL-1ß-driven neuroinflammation during autoimmune encephalomyelitis in mice.

Growing evidence supports a role for IL-1 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), but how it impacts neuroinflammation is poorly understood. We show that susceptibility to EAE requires activation of IL-1R1 on radiation-resistant cells via IL-1ß secreted by bone marrow-derived cells. Neutrophils and monocyte-derived macrophages (MDMs) are the main source of IL-1ß and produce this cytokine as a result of their transmigration across the inflamed blood-spinal cord barrier. IL-1R1 expression in the spinal cord is found in endothelial cells (ECs) of the pial venous plexus. Accordingly, leukocyte infiltration at EAE onset is restricted to IL-1R1(+) subpial and subarachnoid vessels. In response to IL-1ß, primary cultures of central nervous system ECs produce GM-CSF, G-CSF, IL-6, Cxcl1, and Cxcl2. Initiation of EAE or subdural injection of IL-1ß induces a similar cytokine/chemokine signature in spinal cord vessels. Furthermore, the transfer of Gr1(+) cells on the spinal cord is sufficient to induce illness in EAE-resistant IL-1ß knockout (KO) mice. Notably, transfer of Gr1(+) cells isolated from C57BL/6 mice induce massive recruitment of recipient myeloid cells compared with cells from IL-1ß KO donors, and this recruitment translates into more severe paralysis. These findings suggest that an IL-1ß-dependent paracrine loop between infiltrated neutrophils/MDMs and ECs drives neuroinflammation.