Keratinocytes and Activation of TREM-1 Pathway in Cutaneous Leishmaniasis Lesions

Abstract

Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) amplifies the immune response, operating synergistically with Toll-Like Receptors (TLRs) in the production of inflammatory mediators. TREM-1 signaling depends on the adapter protein DAP12, which results in the activation of NFkB, the expression of inflammatory genes, and the release of antimicrobial peptides, such as Beta-defensin 2. We evaluated the activation of the TREM-1 signaling pathways in Cutaneous Leishmaniasis (CL) caused by Leishmania braziliensis and linage human keratinocytes exposed to these parasites since the host immune response against Leishmania plays a critical role in promoting parasite killing but also participates in inflammation and tissue damage. We analyzed publicly available transcriptome data from the lesions of CL patients. In the CL biopsies, we found increased expression of the molecules involved in the TREM-1 pathway. We then validated these findings with RT-qPCR and immunohistochemistry in newly obtained biopsies. Surprisingly, we found a strong labeling of TREM-1 in keratinocytes, prompting the hypothesis that increased TREM-1 activation may be the result of tissue damage. However, increased TREM-1 expression was only seen in human lineage keratinocytes following parasite stimulation. Moreover, no up-regulation of TREM-1 expression was observed in the skin lesions caused by other non-infectious inflammatory diseases. Together, these findings indicate that L. braziliensis (Lb) induces the expression of the TREM-1 receptor in tissue keratinocytes regardless of tissue damage, suggesting that non-immune skin cells may play a role in the inflammatory response of CL.

Análise dos benefícios do desenvolvimento de vacinas contra Leishmaniose em relação ao tratamento clássico

“…Partindo da concepção supracitada, podemos identificar a forte "raiz" imunológica desse acontecimento. O que ocorreu com o botânico Charles pode ser explicado pelo papel importante das células dendríticas nesta reação imunológica, visto que são potentes células apresentadoras de antígenos profissionais (APCs) que ligam efetivamente as respostas inatas e adaptativas pois, ao serem ativadas, sofrem maturação e dão início a respostas imunes pela apresentação de antígenos às células T, mediante complexo maior de histocompatibilidade (MHC) (Nunes et al, 2023).…”

Involvement of TLR9 in priming the immune response in oral papillomatosis induced by low-risk HPV

“…The capacity of HR-HPV to induce tumor transformation by the efficient evasion of all steps in the cascade of innate immune recognition, initiating with down-regulated signaling pathways in the infected Kcs is well documented [ 39 , 46 , 62 , 63 , 64 , 65 ]. As a response, Kcs fail to synthetize proinflammatory cytokines and the activation of APCs is impaired [ 58 , 64 , 65 ].…”

“…In addition to be the target for HPV infection, Kcs are non-professional antigen-presenting cells (APCs) that produce cytokines in response to an event involving changes in the innate immune system; they act to initiate the immune response activating professional APCs, i.e., Langerhans cells in the epithelium, and dendritic cells (DCs) and macrophages, in the connective tissue [ 44 ]. Kcs express pattern recognition receptors (PRRs) able to identify microbial pathogens, pathogen-associated molecular patterns (PAMPs), damage signals (DAMPs) derived from various cells of the host (tumor and dying cells), or products locally released in response to different signals determining inflammation without infection [ 45 , 46 , 47 ]. From all the classes of PRRs, Toll-like receptors (TLRs) are the best characterized.…”

“…The increased expression of TLRs is important for the regression of HPV infection [ 56 ]. Studies show that in lesions induced by LR-HPVs, a significant increase in TLR9 expression is noted, while the expression of other TLRs did not change [ 46 , 55 , 57 , 58 , 59 ].…”

“…Kcs express pattern recognition receptors (PRRs) able to identify microbial pathogens, pathogen-associated molecular patterns (PAMPs), damage signals (DAMPs) derived from various cells of the host (tumor and dying cells), or products locally released in response to different signals determining inflammation without infection [45][46][47]. From all the classes of PRRs, Toll-like receptors (TLRs) are the best characterized.…”