Cathelicidin augments VDR-dependent anti-leishmanial immune response in Indian Post-Kala-Azar Dermal Leishmaniasis.
Das. Sushmita S; Sardar. Abul Hasan AH; Abhishek. Kumar K; Kumar. Ajay A; Rabidas. Vidya Nand VN; Das. Pradeep P
Key Findings
- PKDL patients had low vitamin D, low LL‑37 and low VDR expression.
- Amphotericin B treatment increased VDR‑dependent LL‑37 production in macrophages, likely via IL‑12 up‑regulation.
- 1,25‑vitamin D3 induced LL‑37 through TLR2/IL‑1β signaling, not TLR4.
- Elevated LL‑37 enhanced Amphotericin B’s anti‑leishmanial activity by increasing CD40, p‑STAT1, MHC‑II and shifting the IL‑10/IL‑12 balance toward a Th1 response.
Practical Outcomes
- For biohackers, the take‑away is that maintaining adequate vitamin D may help boost your body’s natural LL‑37 antimicrobial peptide, potentially improving immune defense. However, LL‑37 itself isn’t an over‑the‑counter supplement, and the study’s benefit was seen only when combined with a prescription antifungal drug in a specific disease, so direct self‑administration isn’t advised. Focus on safe vitamin D supplementation (e.g., 1000‑2000 IU daily, depending on blood levels) to support innate immunity.
Summary
The study shows that low vitamin D in patients with a skin form of leishmaniasis is linked to low levels of the antimicrobial peptide LL‑37 and its receptor VDR. Giving vitamin D or the drug Amphotericin B raises LL‑37 in immune cells, and higher LL‑37 makes the drug kill the parasite better by boosting the cells' ability to fight infection.
Abstract
Indian Post kala-azar dermal leishmaniasis (PKDL) is the cutaneous aftermath of visceral leishmaniasis (VL) caused by L. donovani. Vitamin D-regulated cationic antimicrobial peptide cathelicidin (hCAP-18/LL-37) has microbicidal and immunomodulatory role against cutaneous infections, but its role in PKDL remains elusive. Skin snips and blood-derived monocytes of PKDL patients (n=46), before (BT) and after (AT) chemotherapy, were used for this study. Serum vitamin D3 level was evaluated by ELISA. Cathelicidin and vitamin D receptor (VDR) levels were analyzed by real-time PCR and flowcytometry in PKDL patients. The mechanistic effect of cathelicidin on macrophage differentiation and anti-leishmanial activity was assessed through RNA interference techniques followed by subsequent microscopic evaluation of in vitro parasite killing and Th1/Th2 counter-regulation by ELISA/RT-PCR. Low vitamin D3 levels were accompanied with decreased expression of cathelicidin and VDR in PKDL-BT patients. Results suggested positive induction of VDR-dependent cathelicidin in PKDL macrophages by Amphotericin B treatment, which could be due to indirect effect of drug-induced IL12 upregulation. 1,25-Vitamin D3 stimulation induced cathelicidin in PKDL-BT patients through involvement of TLR2/IL-1β, but not TLR4. Cathelicidin also augmented the anti-leishmanial effect and macrophage activating potential of Amphotericin B, attributable to regulation of VDR-dependent enhancement of CD40, p-STAT-I and MHC-II expression leading to regulation of IL10/IL12 balance in PKDL-BT patient macrophages. This study indicates that cathelicidin augments anti-leishmanial macrophage activating property of Amphotericin B in a TLR2/VDR dependent mechanism, and advocate the development of novel adjunct treatment modality of cathelicidin with conventional Amphotericin B in PKDL patients.
Study Information
pubmed
2017
2017-07-12T00:00:00.000Z
10.1016/j.intimp.2017.06.010
14
62