Disruption of monocyte-macrophage differentiation and trafficking by a heme analog during active inflammation.
Disruption of monocyte-macrophage differentiation and trafficking by a heme analog during active inflammation.
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DOI：
10.1038/s41385-021-00474-8
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发表时间：
2022-03
影响因子：
8
通讯作者：
Onyiah JC
中科院分区：
文献类型：
--
作者：
Schaefer REM;Callahan RC;Atif SM;Orlicky DJ;Cartwright IM;Fontenot AP;Colgan SP;Onyiah JC
血红素代谢是炎症反应的关键调节因子。钴原卟啉IX （CoPP）是一种血红素类似物和模拟物，可有效激活NRF2/血红素氧合酶-1 （HO-1）途径，特别是在单核细胞和巨噬细胞中。我们利用小鼠结肠炎模型研究了CoPP对炎症反应的影响。令人惊讶的是，在葡聚糖硫酸钠诱导结肠炎的情况下，髓系HO-1的条件性缺失并不影响结肠炎症反应或CoPP的保护作用。相反，我们揭示了CoPP在活跃的肠道炎症期间引起了相对于结肠的血髓细胞群的矛盾转变。主要的人群变化包括CCR2+Ly6Chi单核细胞到炎症结肠的运输明显减少，尽管这一人群被大量动员到循环中。这导致单核细胞来源的巨噬细胞的结肠扩张和炎症细胞因子的表达显著减少。这些发现与系统性CCL2的显著诱导有关，导致CCL2向结肠的化学引诱剂梯度被破坏，以及循环单核细胞CCR2表达的浓度依赖性抑制。CoPP还诱导巨噬细胞分化为MarcohiHmox1hi抗炎红细胞表型，有助于整体炎症谱的降低。这些发现重新定义了炎症期间血红素代谢的保护作用，并强调了以前未报道的内源性CCL2诱导的免疫抑制机制。在结肠炎模型中，血红素类似物和模拟物触发抗炎CCL2梯度，导致单核细胞相对于体循环向结肠运输的矛盾抑制，以及独立于髓系HO-1的抗炎红细胞巨噬细胞分化。
Heme metabolism is a key regulator of inflammatory responses. Cobalt protoporphyrin IX (CoPP) is a heme analog and mimic that potently activates the NRF2/heme oxygenase-1 (HO-1) pathway, especially in monocytes and macrophages. We investigated the influence of CoPP on inflammatory responses using a murine model of colitis. Surprisingly, conditional deletion of myeloid HO-1 did not impact the colonic inflammatory response or the protective influence of CoPP in the setting of dextran sodium sulphate-induced colitis. Rather, we reveal that CoPP elicits a contradictory shift in blood myeloid populations relative to the colon during active intestinal inflammation. Major population changes include markedly diminished trafficking of CCR2+Ly6Chi monocytes to the inflamed colon, despite significant mobilization of this population into circulation. This resulted in significantly diminished colonic expansion of monocyte-derived macrophages and inflammatory cytokine expression. These findings were linked with significant induction of systemic CCL2 leading to a disrupted CCL2 chemoattractant gradient towards the colon and concentration-dependent suppression of circulating monocyte CCR2 expression. Administration of CoPP also induced macrophage differentiation toward a MarcohiHmox1hi anti-inflammatory erythrophagocytic phenotype, contributing to an overall decreased inflammatory profile. Such findings redefine protective influences of heme metabolism during inflammation, and highlight previously unreported immunosuppressive mechanisms of endogenous CCL2 induction. A heme analog and mimic triggers an anti-inflammatory CCL2 gradient in a model of colitis, resulting in contradictory suppressed trafficking of monocytes to the colon relative to the systemic circulation, as well as anti-inflammatory erythrophagocytic macrophage differentiation, independent of myeloid HO-1.
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影响因子：
64.5
作者：
Haldar M;Kohyama M;So AY;Kc W;Wu X;Briseño CG;Satpathy AT;Kretzer NM;Arase H;Rajasekaran NS;Wang L;Egawa T;Igarashi K;Baltimore D;Murphy TL;Murphy KM
通讯作者：
Murphy KM
DOI：
10.4049/jimmunol.1302647
发表时间：
2015-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Carvallo L;Lopez L;Che FY;Lim J;Eugenin EA;Williams DW;Nieves E;Calderon TM;Madrid-Aliste C;Fiser A;Weiss L;Angeletti RH;Berman JW
通讯作者：
Berman JW
影响因子：
--
作者：
Haringman, Jasper J.;Gerlag, Danielle M.;Tak, Paul P.
通讯作者：
Tak, Paul P.
影响因子：
8
作者：
Konrad, F. M.;Knausberg, U.;Reutershan, J.
通讯作者：
Reutershan, J.
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I