2022 Volume 39 Issue 4 Pages 517-521
While inflammation after cerebral infarction is an essential process for removal and repair of the infarcted area, excessive inflammation induces tissue damage. In rodents, damage–associated molecular patterns (DAMPs) released from injured cells in the early ischemic phase induce cytokine and chemokine production by activating microglia, which subsequently induces infiltration of neutrophil and lymphocytes. However, large–scale clinical trials to inhibit neutrophil (ASTIN) and lymphocytes (ACTION II) showed no apparent improvement in functional outcome. In addition, the SCIL–STROKE trial with an IL1 receptor antagonist reduced IL6 expression but did not improve functional prognosis, suggesting that targeting only one molecule may have limitations. In this context, the selection of molecules and cell types that can regulate multiple cytokine production may be important. In a study of autopsy brains of stroke patients, the infiltration of lymphocytes and neutrophils was very low, and the increase and infiltration of activated microglia/macrophages (M/M) was the major pathological changes. Considering that DAMPs/ toll–like receptor (TLR) signaling is the starting point for microglial activation, regulation of TLR signaling in M/M may be an important therapeutic strategy.
We found that (receptor activator of NF–κB ligand) RANKL/RANK signaling expressed in activated M/M suppresses DAMPs/TLR4 signaling, and MHP1, a partial peptide of RANKL, acts on CD14, a co–receptor for RANK and TLRs, and regulates multiple TLR signals. We reported that it suppresses. The peptide showed certain effects in mouse and monkey cerebral infarction models and could be used in combination with tPA. Furthermore, its effects have been observed in psoriasis and pulmonary fibrosis, where TLRs are pathologically relevant. To achieve more effective peptides, modification of the peptides is currently progressing.
Although drug discovery in the field of acute stroke is challenging, continued research on elucidation of molecular mechanisms and development of drugs that differ from existing ones is important for the development of drugs for stroke regulating inflammation.
