B cell-derived IL-10 suppresses inflammatory disease in Lyn-deficient mice

Abstract

Lyn kinase deficient mice represent a well established genetic model of autoimmune/autoinflammatory disease that resembles systemic lupus erythematosus. We report that IL-10 plays a crucial immunosuppressive role in this model, modulating the inflammatory component of the disease caused by myeloid and T-cell activation. Double-mutant lyn −/− IL-10 −/− mice manifested severe splenomegaly and lymphadenopathy, dramatically increased proinflammatory cytokine production, and severe tissue inflammation. Single-mutant lyn −/− mice showed expansion of IL-10–producing B cells. Interestingly, WT B cells adoptively transferred into lyn −/− mice showed increased differentiation into IL-10–producing B cells that assumed a similar phenotype to endogenous lyn −/− IL-10–producing B cells, suggesting that the inflammatory environment present in lyn −/− mice induces IL-10–producing B-cell differentiation. B cells, but not T or myeloid cells, were the critical source of IL-10 able to reduce inflammation and autoimmunity in double mutant lyn −/− IL-10 −/− mice. IL-10 secretion by B cells was also crucial to sustain transcription factor Forkhead Box P3 (Foxp3) expression in regulatory T cells during disease development. These data reveal a dominant immunosuppressive function of B-cell–derived IL-10 in the Lyn-deficient model of autoimmunity, extending our current understanding of the role of IL-10 and IL-10–producing B cells in systemic lupus erythematosus.

Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation

“…2B). As previously observed, the lyn −/− mice had elevated levels of Th1 (IFN-γ) and Th17 (IL-17), but not Th2 (IL-4 and IL-13) cytokines, as well as increased levels of IL-6, IL12-p40, G-CSF, GM-CSF and a number of chemokines (KC, MIG, MIP-1α/β and IP10) (16). Similar changes were also observed in the lyn f/f Cd11c-cre + animals (Fig.…”

Attenuation of phosphoinositide 3-kinase δ signaling restrains autoimmune disease

“…This suggests a link between autoimmunity and inflammation in susceptible mice. The proinflammatory cytokine IL-6 is elevated in the serum from some aged Lyn À/À mice [16,47], and it has been shown that the increase in myeloid progenitors and myeloid cell expansion is dependent on IL-6 [16]. Interestingly, while IL-6 levels were reduced in p110d þ/KD serum compared to controls, levels were similarly elevated in the serum of some aged Lyn À/À and Lyn À/À p110d þ/KD mice (Fig.…”

“…Since Lyn À/À B cells are the major producers of IL-6 [16], this suggests that this phenotype is unaltered by haploinsufficiency of p110d. The anti-inflammatory cytokine IL-10 has been shown to be increased in the serum of aged Lyn À/À mice [47] where it is believed to play a role in suppressing the inflammatory environment and autoimmune disease development. We have confirmed that IL-10 is elevated in the serum of aged Lyn À/À mice, and have found that it is similarly elevated in the serum of aged Lyn À/À p110d þ/KD mice (Fig.…”

Src family kinases: at the forefront of platelet activation

“…56,57 The phenotype can be partially explained by increased Mpl-mediated Erk1, Erk2, and Akt activation in Lyn-deficient megakaryocytes. SHIP-1 phosphorylation is concomitantly decreased, suggesting that Lyn negatively regulates the Ras/MAPK and PI3K/Akt pathways in a SHIP-1-dependent manner.…”