Matozaki, T. | bioRxiv Science

bioRxiv2020

SIRPalpha on mouse B1 cells restricts lymphoid tissue migration and natural antibody production

The inhibitory immunoreceptor SIRP is expressed on myeloid and neuronal cells and interacts with the broadly expressed CD47. CD47-SIRP interactions form an innate immune checkpoint and its targeting has shown promising results in cancer patients. Here, we report expression of SIRP on B1 lymphocytes, a non-conventional subpopulation of murine B cells responsible for the production of natural antibodies. Mice defective in SIRP signaling (SIRP{Delta}CYT mice) displayed an enhanced CD11b/CD18 integrin-dependent B1 cell migration from the peritoneal cavity to the spleen, local B1 cell accumulation, and enhanced circulating natural antibody levels, which was further amplified upon immunization with T-independent type 2 antigen. As natural antibodies are atheroprotective we investigated the involvement of SIRP signaling in atherosclerosis development. Bone marrow (SIRP{Delta}CYT>LDLR-/-) chimaeric mice developed reduced atherosclerosis accompanied by increased natural antibody production. Collectively, our data identify SIRP as a unique B1 cell inhibitory receptor acting to control B1 cell migration, and imply SIRP as a potential therapeutic target in atherosclerosis.

immunology↗

bioRxiv2018

Microglial SIRPα regulates the emergence of CD11c+ microglia and demyelination damage in white matter

A characteristic subset of microglia expressing CD11c appears in response to brain damage. However, the functional role of CD11c+ microglia, as well as the mechanism of its induction, are poorly understood. Here we report that the genetic ablation of signal regulatory protein (SIRP), a membrane protein, induced CD11c+ microglia in the brain white matter. Mice lacking CD47, a physiological ligand of SIRP, and microglia-specific SIRP knockout mice exhibited the same phenotype, suggesting the interaction between microglial SIRP and CD47 on neighbouring cells suppressed the emergence of CD11c+ microglia. A lack of SIRP did not cause detectable damage in the white matter, but resulted in the increased expression of genes characteristic of the repair phase after demyelination. In addition, cuprizone-induced demyelination was alleviated by the microglia-specific ablation of SIRP. Thus, microglial SIRP suppresses the induction of CD11c+ microglia that have the potential to accelerate the repair of damaged white matter.

neuroscience↗