Acute-Phase Protein Hemopexin Is a Negative Regulator of Th17 Response and Experimental Autoimmune Encephalomyelitis Development

Abstract

Hemopexin (Hx) is an acute-phase protein synthesized by hepatocytes in response to the proinflammatory cytokines IL-6, IL-1β, and TNF-α. Hx is the plasma protein with the highest binding affinity to heme and controls heme-iron availability in tissues and also in T lymphocytes, where it modulates their responsiveness to IFN-γ. Recent data have questioned regarding an anti-inflammatory role of Hx, a role that may be both heme-binding dependent and independent. The aim of this study was to investigate the role of Hx in the development of a T cell–mediated inflammatory autoimmune response. During experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis, Hx content in serum increased and remained high. When EAE was induced in Hx knockout (Hx−/−) mice, they developed a clinically earlier and exacerbated EAE compared with wild-type mice, associated to a higher amount of CD4+-infiltrating T cells. The severe EAE developed by Hx−/− mice could be ascribed to an enhanced expansion of Th17 cells accounting for both a higher disposition of naive T cells to differentiate toward the Th17 lineage and a higher production of Th17 differentiating cytokines IL-6 and IL-23 by APCs. When purified human Hx was injected in Hx−/− mice before EAE induction, Th17 expansion, as well as disease severity, were comparable with those of wild-type mice. Taken together, these data indicate that Hx has a negative regulatory role in Th17-mediated inflammation and prospect its pharmacological use to limit the expansion of this cell subset in inflammatory and autoimmune disease.

Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease

“…Importantly, by scavenging free heme, Hx prevents hemeinduced M1 macrophage polarization and thus avoids both TLR4 activation and ROS formation. These observations are in line with recent studies demonstrating antioxidant and anti-inflammatory properties of Hx, 5,6,[66][67][68] as well as its ability to prevent heme-triggered TLR4 activation and TNFa production. 17,54 Thus, Hx treatment provides a clear advantage over pharmacologic approaches in that it combines antioxidant properties together with inhibitory effects on the proinflammatory pathways induced by heme.…”

Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases

“…Hx therapy in Hx-null mice before EAE induction reduced the Th17 expansion, as well as disease severity, and was comparable with those of wild-type mice. Taken together, these data indicate that Hx has a negative regulatory effect in Th17-mediated inflammation and propose hemopexin’s therapy to limit the expansion of this cell subset in inflammatory and autoimmune diseases (28). …”

Evidence for a Role of Nerve Injury in Painful Intervertebral Disc Degeneration: A Cross-Sectional Proteomic Analysis of Human Cerebrospinal Fluid

“…14 Hemopexin levels are elevated in injured nerves, 65 remain elevated in states of ongoing Wallerian degeneration, 66, 107 and have been shown to negatively regulate inflammatory Th17 T cell responses. 93 Likewise, nerve injury also alters T cell responses. 69, 79 Consistent with our observation of increased hemopexin in CSF of LBP patients, others have observed a reduction in Th17 T cells in LBP patients and in chronic neuropathic pain patients.…”