MIR337-3p Enhances Mycobacterial Pathogenicity Involving TLR4/MYD88 and STAT3 Signals, Impairing VDR Antimicrobial Response and Fast-Acting Immunity
Active form of vitamin D (VitD) enhances human innate immunity against Mycobacterium tuberculosis (Mtb) infection. Our previous studies showed that MIR337-3p was highly expressed in lymphocytes of tuberculosis (TB) patients. Here, we identified the mechanism of MIR337-3p in the regulation of fast-ac...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-11-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.739219/full |
| _version_ | 1818722118593937408 |
|---|---|
| author | Shanshan Liang Guixian Huang Tian Wu Ying Peng Xi Liu Xuejiao Ji Wei Sha Feifei Wang Ling Shen Hongbo Shen |
| author_facet | Shanshan Liang Guixian Huang Tian Wu Ying Peng Xi Liu Xuejiao Ji Wei Sha Feifei Wang Ling Shen Hongbo Shen |
| author_sort | Shanshan Liang |
| collection | DOAJ |
| description | Active form of vitamin D (VitD) enhances human innate immunity against Mycobacterium tuberculosis (Mtb) infection. Our previous studies showed that MIR337-3p was highly expressed in lymphocytes of tuberculosis (TB) patients. Here, we identified the mechanism of MIR337-3p in the regulation of fast-acting anti-TB immunity by inhibiting VitD-dependent antimicrobial response pathways. While high-level MIR337-3p expression was induced by mycobacterial infection in cellular models and mice, TB patients exhibited significantly increased MIR337-3p in CD14+ monocytes/macrophages, innate-like Vγ2+ T cells, and CD8+ lymphocytes containing natural killer (NK)/innate lymphoid cells. MIR337-3p promoted the mycobacterial entry/infection and replication/growth in host target cells: macrophages and lung epithelial cells. Such MIR337-3p-enhanced pathogenicity coincided with the MIR337-3p depression of VitD-dependent antimicrobial response of cytochrome P450, family 27, subfamily b, polypeptide 1 (CYP27B1)/Beta-defensin 4 (DEFB4A)/ cathelicidin antimicrobial peptide CAMP pathways. Surprisingly, single MIR337-3p species could specifically target both the Toll-like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) 3′-untranslated regions (UTRs) to depress the TLR4/MYD88 and STAT3 signals and impair either of the two signals inhibiting the VitD-dependent antimicrobial pathways in macrophages. Concurrently, human peripheral blood mononuclear cells (PBMCs) expressing high-level MIR337-3p exhibited a reduced ability of innate cell populations to mount fast-acting cellular immunity against intracellular mycobacterial infection. Furthermore, a higher expression of Mir337-3p after mycobacterial infection of mice coincided with much greater colony-forming unit (CFU) counts in lungs and even the death of infected animals, whereas Mir337-3p inhibitor treatment of infected mice reduced Mir337-3p levels and reversed Mir337-3p-mediated increases in CFU counts. Thus, TB-driven single MIR337-3p species could specifically target/impair both TLR4/MYD88 and STAT3 activation signals, inhibiting VitD-dependent antimicrobial response and fast-acting anti-TB immunity, leading to enhanced pathogenicity. |
| first_indexed | 2024-12-17T20:49:33Z |
| format | Article |
| id | doaj.art-92613dd1b3004f67ba2d6c9aa61655b6 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T20:49:33Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-92613dd1b3004f67ba2d6c9aa61655b62022-12-21T21:33:04ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-11-011210.3389/fimmu.2021.739219739219MIR337-3p Enhances Mycobacterial Pathogenicity Involving TLR4/MYD88 and STAT3 Signals, Impairing VDR Antimicrobial Response and Fast-Acting ImmunityShanshan Liang0Guixian Huang1Tian Wu2Ying Peng3Xi Liu4Xuejiao Ji5Wei Sha6Feifei Wang7Ling Shen8Hongbo Shen9Clinic and Research Center of Tuberculosis, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Institute for Advanced Study, Tongji University School of Medicine, Shanghai, ChinaClinic and Research Center of Tuberculosis, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Institute for Advanced Study, Tongji University School of Medicine, Shanghai, ChinaClinic and Research Center of Tuberculosis, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Institute for Advanced Study, Tongji University School of Medicine, Shanghai, ChinaClinic and Research Center of Tuberculosis, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Institute for Advanced Study, Tongji University School of Medicine, Shanghai, ChinaClinic and Research Center of Tuberculosis, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Institute for Advanced Study, Tongji University School of Medicine, Shanghai, ChinaClinic and Research Center of Tuberculosis, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Institute for Advanced Study, Tongji University School of Medicine, Shanghai, ChinaClinic and Research Center of Tuberculosis, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Institute for Advanced Study, Tongji University School of Medicine, Shanghai, ChinaKey Laboratory of Medical Molecular Virology (Ministry of Education of the people's Republic of China (MOE)/National Health Commission of the people's Republic of China (NHC)/Chinese Academy of Medical Sciences (CAMS)), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, ChinaDepartment of Microbiology & Immunology and Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, IL, United StatesClinic and Research Center of Tuberculosis, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Institute for Advanced Study, Tongji University School of Medicine, Shanghai, ChinaActive form of vitamin D (VitD) enhances human innate immunity against Mycobacterium tuberculosis (Mtb) infection. Our previous studies showed that MIR337-3p was highly expressed in lymphocytes of tuberculosis (TB) patients. Here, we identified the mechanism of MIR337-3p in the regulation of fast-acting anti-TB immunity by inhibiting VitD-dependent antimicrobial response pathways. While high-level MIR337-3p expression was induced by mycobacterial infection in cellular models and mice, TB patients exhibited significantly increased MIR337-3p in CD14+ monocytes/macrophages, innate-like Vγ2+ T cells, and CD8+ lymphocytes containing natural killer (NK)/innate lymphoid cells. MIR337-3p promoted the mycobacterial entry/infection and replication/growth in host target cells: macrophages and lung epithelial cells. Such MIR337-3p-enhanced pathogenicity coincided with the MIR337-3p depression of VitD-dependent antimicrobial response of cytochrome P450, family 27, subfamily b, polypeptide 1 (CYP27B1)/Beta-defensin 4 (DEFB4A)/ cathelicidin antimicrobial peptide CAMP pathways. Surprisingly, single MIR337-3p species could specifically target both the Toll-like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) 3′-untranslated regions (UTRs) to depress the TLR4/MYD88 and STAT3 signals and impair either of the two signals inhibiting the VitD-dependent antimicrobial pathways in macrophages. Concurrently, human peripheral blood mononuclear cells (PBMCs) expressing high-level MIR337-3p exhibited a reduced ability of innate cell populations to mount fast-acting cellular immunity against intracellular mycobacterial infection. Furthermore, a higher expression of Mir337-3p after mycobacterial infection of mice coincided with much greater colony-forming unit (CFU) counts in lungs and even the death of infected animals, whereas Mir337-3p inhibitor treatment of infected mice reduced Mir337-3p levels and reversed Mir337-3p-mediated increases in CFU counts. Thus, TB-driven single MIR337-3p species could specifically target/impair both TLR4/MYD88 and STAT3 activation signals, inhibiting VitD-dependent antimicrobial response and fast-acting anti-TB immunity, leading to enhanced pathogenicity.https://www.frontiersin.org/articles/10.3389/fimmu.2021.739219/fullMycobacterium tuberculosismiR337-3pvitamin D3TLR4STAT3CYP27B1 |
| spellingShingle | Shanshan Liang Guixian Huang Tian Wu Ying Peng Xi Liu Xuejiao Ji Wei Sha Feifei Wang Ling Shen Hongbo Shen MIR337-3p Enhances Mycobacterial Pathogenicity Involving TLR4/MYD88 and STAT3 Signals, Impairing VDR Antimicrobial Response and Fast-Acting Immunity Frontiers in Immunology Mycobacterium tuberculosis miR337-3p vitamin D3 TLR4 STAT3 CYP27B1 |
| title | MIR337-3p Enhances Mycobacterial Pathogenicity Involving TLR4/MYD88 and STAT3 Signals, Impairing VDR Antimicrobial Response and Fast-Acting Immunity |
| title_full | MIR337-3p Enhances Mycobacterial Pathogenicity Involving TLR4/MYD88 and STAT3 Signals, Impairing VDR Antimicrobial Response and Fast-Acting Immunity |
| title_fullStr | MIR337-3p Enhances Mycobacterial Pathogenicity Involving TLR4/MYD88 and STAT3 Signals, Impairing VDR Antimicrobial Response and Fast-Acting Immunity |
| title_full_unstemmed | MIR337-3p Enhances Mycobacterial Pathogenicity Involving TLR4/MYD88 and STAT3 Signals, Impairing VDR Antimicrobial Response and Fast-Acting Immunity |
| title_short | MIR337-3p Enhances Mycobacterial Pathogenicity Involving TLR4/MYD88 and STAT3 Signals, Impairing VDR Antimicrobial Response and Fast-Acting Immunity |
| title_sort | mir337 3p enhances mycobacterial pathogenicity involving tlr4 myd88 and stat3 signals impairing vdr antimicrobial response and fast acting immunity |
| topic | Mycobacterium tuberculosis miR337-3p vitamin D3 TLR4 STAT3 CYP27B1 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.739219/full |
| work_keys_str_mv | AT shanshanliang mir3373penhancesmycobacterialpathogenicityinvolvingtlr4myd88andstat3signalsimpairingvdrantimicrobialresponseandfastactingimmunity AT guixianhuang mir3373penhancesmycobacterialpathogenicityinvolvingtlr4myd88andstat3signalsimpairingvdrantimicrobialresponseandfastactingimmunity AT tianwu mir3373penhancesmycobacterialpathogenicityinvolvingtlr4myd88andstat3signalsimpairingvdrantimicrobialresponseandfastactingimmunity AT yingpeng mir3373penhancesmycobacterialpathogenicityinvolvingtlr4myd88andstat3signalsimpairingvdrantimicrobialresponseandfastactingimmunity AT xiliu mir3373penhancesmycobacterialpathogenicityinvolvingtlr4myd88andstat3signalsimpairingvdrantimicrobialresponseandfastactingimmunity AT xuejiaoji mir3373penhancesmycobacterialpathogenicityinvolvingtlr4myd88andstat3signalsimpairingvdrantimicrobialresponseandfastactingimmunity AT weisha mir3373penhancesmycobacterialpathogenicityinvolvingtlr4myd88andstat3signalsimpairingvdrantimicrobialresponseandfastactingimmunity AT feifeiwang mir3373penhancesmycobacterialpathogenicityinvolvingtlr4myd88andstat3signalsimpairingvdrantimicrobialresponseandfastactingimmunity AT lingshen mir3373penhancesmycobacterialpathogenicityinvolvingtlr4myd88andstat3signalsimpairingvdrantimicrobialresponseandfastactingimmunity AT hongboshen mir3373penhancesmycobacterialpathogenicityinvolvingtlr4myd88andstat3signalsimpairingvdrantimicrobialresponseandfastactingimmunity |