The effect of systemic corticosteroid therapy on the expression of toll-like receptor 2 and toll-like receptor 4 in the cutaneous lesions of leprosy Type 1 reactions

Walker, Stephen L.; Atkinson, Sara E.; Khadge, Saraswoti; Macdonald, Murdo; Neupane, Kapil Dev; Ranjit, Chaman; Sapkota, Bishwa Raj; Dhakal, Sushmita; Hawksworth, Rachel A; Mahat, Kishori; Ruchal, Shudan; Hamal, Sushma; Hagge, Deanna A.; Lockwood, Diana N J

doi:10.1111/j.1365-2133.2012.10891.x

Cited by 12 publications

(11 citation statements)

References 19 publications

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“…60,61 Clinical studies have shown that TLR2 and 4 are downregulated in leprosy patients undergoing successful corticosteroid therapy, which may contribute to the reversal reaction of leprosy. 62 …”

Section: Discussionmentioning

confidence: 99%

Phagocytosed Clofazimine Biocrystals Can Modulate Innate Immune Signaling by Inhibiting TNFα and Boosting IL-1RA Secretion

et al. 2015

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Clofazimine (CFZ) is an FDA-approved leprostatic and anti-inflammatory drug that massively accumulates in macrophages, forming insoluble, intracellular crystal-like drug inclusions (CLDIs) during long-term oral dosing. Interestingly, when added to cells in vitro, soluble CFZ is cytotoxic because it depolarizes mitochondria and induces apoptosis. Accordingly, we hypothesized that in vivo, macrophages detoxify CFZ by sequestering it in CLDIs. To test this hypothesis, CLDIs of CFZ-treated mice were biochemically isolated, and then incubated with macrophages in vitro. The cell biological effects of phagocytosed CLDIs were compared to those of soluble CFZ. Unlike soluble CFZ, phagocytosis of CLDIs did not lead to mitochondrial destabilization or apoptosis. Rather, CLDIs altered immune signaling response pathways downstream of Toll-like receptor (TLR) ligation, leading to enhanced interleukin-1 receptor antagonist (IL-1RA) production, dampened NF-κB activation and tissue necrosis factor alpha (TNFα) production, and ultimately decreased TLR expression levels. In aggregate, our results constitute evidence that macrophages detoxify soluble CFZ by sequestering it in a biocompatible, insoluble form. The altered cellular response to TLR ligation suggests that CLDI formation may also underlie CFZ’s anti-inflammatory activity.

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Section: Discussionmentioning

confidence: 99%

Phagocytosed Clofazimine Biocrystals Can Modulate Innate Immune Signaling by Inhibiting TNFα and Boosting IL-1RA Secretion

et al. 2015

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“…Macrophages from non-vaccinated healthy donors treated with BCG present reduced TLR4 expression suggesting a role of TLR in the protective effect of BCG. Associated with this, the treatment of reversal reaction with corticosteroids decrease gene and protein expression of both TLR2 and TLR4 in skin lesion cells ( 139 ), indicating the involvement of receptors also in triggering the inflammatory process. A study linking the innate immunity pathways with the development of ENL suggested that recognition of DNA by TLR9 constitutes a major inflammatory pathway activated during ENL ( 140 ).…”

Section: Manipulation Of Innate Immunity By M Lepraementioning

confidence: 99%

Innate Immune Responses in Leprosy

et al. 2018

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Leprosy is an infectious disease that may present different clinical forms depending on host immune response to Mycobacterium leprae. Several studies have clarified the role of various T cell populations in leprosy; however, recent evidences suggest that local innate immune mechanisms are key determinants in driving the disease to its different clinical manifestations. Leprosy is an ideal model to study the immunoregulatory role of innate immune molecules and its interaction with nervous system, which can affect homeostasis and contribute to the development of inflammatory episodes during the course of the disease. Macrophages, dendritic cells, neutrophils, and keratinocytes are the major cell populations studied and the comprehension of the complex networking created by cytokine release, lipid and iron metabolism, as well as antimicrobial effector pathways might provide data that will help in the development of new strategies for leprosy management.

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“…Although TLR2 expression was significantly increased in cells from skin lesions, analysis of M. leprae -stimulated monocytes did not shown differences between cells from WR and T1R groups (not shown), suggesting that there is a modulation of local immune response. A previous study has described TLR2 polymorphisms associated with reversal reaction ( 38 ) and analysis of skin cells from patients with reversal reaction demonstrated that corticosteroids may reduce both gene and protein expression of TLR2 ( 39 ). Our present study demonstrated that in patients that develop reversal reaction in the future (T1R), TLR2 is modulated differentially even before the appearance of the clinical symptoms of the reactional episode.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Impairment Is Associated With Increased Inflammasome Activation and Reversal Reaction Development in Multibacillary Leprosy

et al. 2018

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Leprosy reactions are responsible for incapacities in leprosy and represent the major cause of permanent neuropathy. The identification of biomarkers able to identify patients more prone to develop reaction could contribute to adequate clinical management and the prevention of disability. Reversal reaction may occur in unstable borderline patients and also in lepromatous patients. To identify biomarker signature profiles related with the reversal reaction onset, multibacillary patients were recruited and classified accordingly the occurrence or not of reversal reaction during or after multidrugtherapy. Analysis of skin lesion cells at diagnosis of multibacillary leprosy demonstrated that in the group that developed reaction (T1R) in the future there was a downregulation of autophagy associated with the overexpression of TLR2 and MLST8. The autophagy impairment in T1R group was associated with increased expression of NLRP3, caspase-1 (p10) and IL-1β production. In addition, analysis of IL-1β production in serum from multibacillary patients demonstrated that patients who developed reversal reaction have significantly increased concentrations of IL-1β at diagnosis, suggesting that the pattern of innate immune responses could predict the reactional episode outcome. In vitro analysis demonstrated that the blockade of autophagy with 3-methyladenine (3-MA) in Mycobacterium leprae-stimulated human primary monocytes increased the assembly of NLRP3 specks assembly, and it was associated with an increase of IL-1β and IL-6 production. Together, our data suggest an important role for autophagy in multibacillary leprosy patients to avoid exacerbated inflammasome activation and the onset of reversal reaction.

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The effect of systemic corticosteroid therapy on the expression of toll-like receptor 2 and toll-like receptor 4 in the cutaneous lesions of leprosy Type 1 reactions

Abstract: This is the first study to examine the expression of TLR2 and TLR4 in vivo in individuals experiencing leprosy Type 1 reactions. The data support the possibility of an important role for TLR2 and TLR4 in the pathogenesis of this important complication of leprosy.

Cited by 12 publications

References 19 publications

Phagocytosed Clofazimine Biocrystals Can Modulate Innate Immune Signaling by Inhibiting TNFα and Boosting IL-1RA Secretion

Phagocytosed Clofazimine Biocrystals Can Modulate Innate Immune Signaling by Inhibiting TNFα and Boosting IL-1RA Secretion

Innate Immune Responses in Leprosy

Autophagy Impairment Is Associated With Increased Inflammasome Activation and Reversal Reaction Development in Multibacillary Leprosy

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