Research team led by the University of Tsukuba identifies a role for spleen marginal zone B lymphocytes in intensifying the inflammatory response to endotoxins through cytokine production

The inability to adequately respond to infection can cause a whole-body state of inflammation known as sepsis. This can eventually lead to systemic inflammatory response syndrome (SIRS), and even death. White blood cells known as B lymphocytes (B cells) produce antibodies in response to infections such as blood-borne pathogens. B cells of the marginal zone (MZ), which separates circulating blood from spleen lymphoid tissue, contribute to this early immune response, but their role in inflammation has remained unclear.

A research team led by Akira Chiba at the University of Tsukuba has now revealed that MZ B cells also produce the signaling proteins cytokines and chemokines involved in inflammatory responses. They recently reported the results of their study in Nature Communications.

Lipopolysaccharides (LPS) are endotoxic products from Gram-negative bacteria that can trigger SIRS. The researchers showed that mice injected with LPS from E. coli were more resistant to endotoxic shock and lived longer if they lacked MZ B cells, suggesting these cells' crucial role in inflammatory response against LPS. MZ B cells were found to produce large quantities of the inflammatory cytokine interleukin (IL)-6, as well as some chemokines, in response to LPS stimulation.

The researchers experimented with blocking the IL-6 function slightly before or a few hours after the LPS injection. "We found that mice were protected against endotoxic shock and survived for longer if IL-6 signaling was stopped at the later stage," lead author Shin-ichiro Honda says. "This is significant in developing treatments for sepsis." After examining the signaling process in greater detail, another protein of the immune system, Toll-like receptor 4 (TLR4), was shown to be necessary for IL-6 production; LPS directly stimulates MZ B cells via TLR4, leading to the production.

Fcα/µR is mainly expressed on lymphoid tissue immune cells, where it acts as a receptor for IgA and IgM antibodies. It is also expressed on MZ B cells, but its role there was unknown. The researchers studied in Fcα/µR-deficient mice and found that their MZ B cells produced much less IL-6 in response to LPS than those of control mice. "We observed that a physical association with Fcα/µR was required for forming the TLR4 complex and IL-6 production in response to LPS," corresponding author Akira Shibuya explains. MZ B cells therefore emerge as a regulator of immune responses with a strong pro-inflammatory role in IL-6 production in endotoxic shock.

Spleen MZ B cells contribute to inflammatory response against endotoxins
B cells from the marginal zone (MZ) of the spleen produce high levels of the pro-inflammatory cytokine interleukin-6 (IL-6) in response to bacterial endotoxins. This response is coordinated by a signaling reaction involving TLR4 and Fcα/µR, and leads to systemic inflammation and endotoxic shock.

Original Paper

Shin-ichiro Honda, Kazuki Sato, Naoya Totsuka, Satoshi Fujiyama, Manabu Fujimoto, Kensuke Miyake, Chigusa Nakahashi-Oda, Satoko Tahara-Hanaoka, Kazuko Shibuya & Akira Shibuya, Nature Communications, Marginal zone B cells exacerbate endotoxin shock via interleukin-6 secretion induced by Fcα/µR-coupled TLR4 signalling. DOI: 10.1038/ncomms11498