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We previously showed that PWH with CWP have increased hemolysis and elevated plasma levels of cell-free heme, which correlate with low endogenous opioid levels in leukocytes. Further, we demonstrated that cell-free heme impairs \u03b2-endorphin synthesis\/release from leukocytes. However, the cellular mechanisms by which heme dampens \u03b2-endorphin production are inconclusive. The current hypothesis is that heme-dependent TLR4 activation and macrophage polarization to the M1 phenotype mediate this phenomenon. Our novel findings showed that PWH with CWP have elevated M1-specific macrophage chemokines (ENA-78, GRO-\u03b1, and IP-10) in plasma. In vitro, hemin-induced polarization of M0 and M2 macrophages to the M1 phenotype with low \u03b2-endorphins was mitigated by treating cells with the TLR4 inhibitor, TAK-242. Similarly, in vivo phenylhydrazine hydrochloride (PHZ), an inducer of hemolysis, injected into C57Bl\/6 mice increased the M1\/M2 cell ratio and reduced \u03b2-endorphin levels. However, treating these animals with the heme-scavenging protein hemopexin (Hx) or TAK-242 reduced the M1\/M2 ratio and increased \u03b2-endorphins. Furthermore, Hx attenuated heme-induced mechanical, heat, and cold hypersensitivity, while TAK-242 abrogated hypersensitivity to mechanical and heat stimuli. Overall, these results suggest that heme-mediated TLR4 activation and M1 polarization of macrophages correlate with impaired endogenous opioid homeostasis and hypersensitivity in people with HIV.<\/jats:p>","DOI":"10.3390\/cells12121565","type":"journal-article","created":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T01:38:41Z","timestamp":1686101921000},"page":"1565","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Heme-Induced Macrophage Phenotype Switching and Impaired Endogenous Opioid Homeostasis Correlate with Chronic Widespread Pain in HIV"],"prefix":"10.3390","volume":"12","author":[{"given":"Tanima","family":"Chatterjee","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, PBMR 230, 901 19th Street South, Birmingham, AL 35205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itika","family":"Arora","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology and the Reproductive Sciences Center, Cincinnati Children\u2019s Hospital, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilly B.","family":"Underwood","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, PBMR 230, 901 19th Street South, Birmingham, AL 35205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry L.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, PBMR 230, 901 19th Street South, Birmingham, AL 35205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Xavier","family":"Masjoan Juncos","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, PBMR 230, 901 19th Street South, Birmingham, AL 35205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya L.","family":"Heath","sequence":"additional","affiliation":[{"name":"Division of Infectious Disease, University of Alabama at Birmingham, Birmingham, AL 35205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8159-1310","authenticated-orcid":false,"given":"Burel R.","family":"Goodin","sequence":"additional","affiliation":[{"name":"Washington University Pain Center, Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO 63130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7192-1569","authenticated-orcid":false,"given":"Saurabh","family":"Aggarwal","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, PBMR 230, 901 19th Street South, Birmingham, AL 35205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/j.jpain.2011.04.002","article-title":"Occurrence and characteristics of chronic pain in a community-based cohort of indigent adults living with hiv infection","volume":"12","author":"Miaskowski","year":"2011","journal-title":"J. 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