We have also addressed a fundamental question regarding how HS globally regulates PMN infiltration in the lungs. We have shown that HS, through alarmin HMGB1, induced IL-23 secretion from macrophages in an autocrine and TLR4 signaling-dependent manner. In turn, IL-23, through an IL-17-G-CSF-mediated mechanism, induced PMN egress from bone marrow. Therefore a sustained and HS-primed migration of PMN was maintained. We have also shown that β-adrenergic-receptor activation by catecholamine of macrophages mediated the HS-induced release of HMGB1. These data indicate that HS, a global ischemia/ reperfusion stimulus, regulates PMN mobilization through a series of interacting pathways that include neuroendocrine and both innate and acquired immune systems (131) .