Here, we review the molecular mechanisms controlling IL-10 expression in B cells, and the evidence that IL-10-producing B cells play a protective role in human autoimmune diseases, underlying the relevance of this immunosuppressive axis for therapy.
IL-10 is the most important cytokine in suppressing pro-inflammatory responses in all kinds of autoimmune diseases and limiting excessive immune responses.
The cytokine IL-10 is a key anti-inflammatory mediator ensuring protection of a host from over-exuberant responses to pathogens and microbiota, while playing important roles in other settings as sterile wound healing, autoimmunity, cancer, and homeostasis.
IL-10 is a suppressive cytokine that has been implicated in the pathophysiology of autoimmune disorders and can be produced by different cell types such as regulatory B-cells.
Taken together, by enhancing IL-10 production and suppressing Th17 cells, the SCFA pentanoate might be of therapeutic relevance for inflammatory and autoimmune diseases.
In MS and other autoimmune diseases decreased frequency and functionality of Breg cells correlate with disease activity and the percentage of IL-10-producing Breg cells decreases during relapse and normalizes in remission.
However, TGF-β and IL-10 also have pleiotropic effects and induce humoral immune responses depending on conditions, and thus their therapeutic application to autoimmune diseases remains limited.
Despite growing evidence highlighting the relevance of increasing IL-10-producing B cells (B10<sup>+</sup>cells) in autoimmune diseases, their functions in patients are still unknown.
The deleterious amino acid substitution mutations in IL-10 receptor alpha gene are most frequently reported in several autoimmune diseases including early onset-inflammatory bowel disease (IBD).
On the other hand, the severity of the autoimmune diseases has been proven to be greater in the presence of high blood levels of IL-17, TNF-alpha, IL-6, IL-1-beta, IFN-gamma, and IL-18, in association with low levels of TGF-beta and IL-10.
Several studies attempted to investigate the role of various flavonoids mainly in experimental models of autoimmune diseases, especially in the context of their potential effect on the increase of regulatory T cells (Tregs) and their ability to stimulate an overexpression of anti-inflammatory cytokines, in particular that of IL-10.
Here we found that c-Maf regulated IL-10 production in CD4<sup>+</sup> T cells in disease models involving the T<sub>H</sub>1 subset of helper T cells (malaria), T<sub>H</sub>2 cells (allergy) and T<sub>H</sub>17 cells (autoimmunity) in vivo.
Recently, it has been characterized as CD1d<sup>hi</sup> CD5<sup>+</sup> regulatory B cell subpopulation able to produce IL-10, and the loss of these cells exacerbates the autoimmunity in murine models.
Regulatory B cells (Bregs) play a crucial role in immunological tolerance primarily through the production of IL-10 in many diseases including autoimmune disorders, allergy, infectious diseases, and cancer.
Taken together, this study demonstrates the key function of the hypoxia-associated transcription factor HIF-1α in driving IL-10 expression in CD1d<sup>hi</sup>CD5<sup>+</sup> B cells, and in controlling their protective activity in autoimmune disease.
Furthermore, we demonstrated that IL-35-producing and IL-10-producing Tregs have a different activation status, do not share the same geographic locations in secondary lymphoid organs, and work in a complementary way to prevent autoimmunity.
As cytokines are prime drug targets, IL-10 family cytokines provide great opportunities for the treatment of autoimmune diseases, tissue damage, and cancer.
These results show that SHIP-1 is required for the maintenance of B10 cells and production of IL-10, and collectively suggests that SHIP-1 could be a new potential therapeutic target for the treatment of autoimmune diseases.