**3.1. Overview**

Neutrophils and macrophages produce pro‐inflammatory cytokines, including interleukins 1 alpha and beta (IL‐1α and β) and tumor necrosis factor alpha (TNF‐α), chemokines, matrix proteases. These materials help to destroy invading bacteria and virus. However, invaded tissue also be damaged by these inflammatory reactions. Once microorganisms are cleared by immune system, the invaded tissue is repaired to healthy state. However, some microorgan‐ isms such as hepatitis C virus keep staying in host tissue and repeatedly attack host tissue, which induces fatal tissue damages finally. In sterile inflammation similar phenomena occur. External stimuli, which destroy tissue cells, produce DAMPs and induce sterile inflammation. Because immune cells secrete toxic proteases to kill microorganisms, the same immune cells destroy tissue cells.If external stimuli are limited,repair system such as M2 macrophages work to repair tissue damages and returns to normal condition. However, repeated stimuli may induce next inflammation before tissue repair and will induce chronic tissue damages, which cannot be recovered. In these processes, auto reactive T cells and B cells are engaged.

## **3.2. Bleomycin (BLM)‐induced murine model of experimental systemic sclerosis**

BLM is a glycopeptide produced by the bacterium Streptomyces verticillus, which can cleave DNA, and it is widely used as an anti‐tumor agent for various types of malignancies [10]. Thus BLM administration destroys tissue cells and induces sterile inflammation. We examined the effects of repeated injection of BLM to adult mice. When BLM was injected into the shaved backs of adult C3H or BALB/c mice (100 μg/mouse) 5 days per week for 3 weeks, not only skin fibrosis, but also esophageal and gastric damage related to fibrosis were observed. Injection of BLM induced innate immune inflammation, which did not resolve. Dendritic cells, which engulfed dead cells, transferred auto antigens to T cells. Transfer of CD4+ T cells from BLM‐ treated BALB/c mice induced the same pathological changes and antibody production in untreated‐BALB/c nude mice. Th17 cells secret IL17, which stimulated innate immune cells to damage tissues [11].
