PMID- 37577587
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230814
DP  - 2023 Aug 2
TI  - Immunoregulatory macrophages modify local pulmonary immunity and ameliorate 
      hypoxic-pulmonary hypertension.
LID - 2023.07.31.551394 [pii]
LID - 10.1101/2023.07.31.551394 [doi]
AB  - RATIONALE: Macrophages play a central role in the onset and progression of 
      vascular disease in pulmonary hypertension (PH) and cell-based immunotherapies 
      aimed at treating vascular remodeling are lacking. OBJECTIVE: To evaluate the 
      effect of pulmonary administration of macrophages modified to have an 
      anti-inflammatory/pro-resolving phenotype in attenuating early pulmonary 
      inflammation and progression of experimentally induced PH. METHODS: Mouse bone 
      marrow derived macrophages (BMDMs) were polarized in vitro to a regulatory (M2 
      (reg) ) phenotype. M2 (reg) profile and anti-inflammatory capacity were assessed 
      in vitro upon lipopolysaccharide (LPS)/interferon-gamma (IFNgamma) restimulation, before 
      their administration to 8- to 12-week-old mice. M2 (reg) protective effect was 
      tested at early (2 to 4 days) and late (4 weeks) time points during hypoxia (8.5% 
      O (2) ) exposure. Levels of inflammatory markers were quantified in alveolar 
      macrophages and whole lung, while PH development was ascertained by right 
      ventricular systolic pressure (RSVP) and right ventricular hypertrophy (RVH) 
      measurements. Bronchoalveolar lavage (BAL) from M2 (reg) -transplanted hypoxic 
      mice was collected, and its inflammatory potential tested on naive BMDMs. 
      RESULTS: M2 (reg) macrophages demonstrated a stable anti-inflammatory phenotype 
      upon a subsequent pro-inflammatory stimulus by maintaining the expression of 
      specific anti-inflammatory markers (Tgfss, Il10 and Cd206) and downregulating the 
      induction of proinflammatory cytokines and surface molecules (Cd86, Il6 and 
      Tnfalpha). A single dose of M2 (regs) attenuated the hypoxic monocytic recruitment 
      and perivascular inflammation. Early hypoxic lung and alveolar macrophage 
      inflammation leading to PH development was significantly reduced and, 
      importantly, M2 (regs) attenuated RVH, RVSP and vascular remodeling at 4 weeks 
      post treatment. CONCLUSIONS: Adoptive transfer of M2 (regs) halts the recruitment 
      of monocytes and modifies the hypoxic lung microenvironment, potentially changing 
      the immunoreactivity of recruited macrophages and restoring normal immune 
      functionality of the lung. These findings provide new mechanistic insights on the 
      diverse role of macrophage phenotype on lung vascular homeostasis that can be 
      explored as novel therapeutic targets.
FAU - Fernandez-Gonzalez, Angeles
AU  - Fernandez-Gonzalez A
AUID- ORCID: 0000-0003-1219-9128
FAU - Mukhia, Amit
AU  - Mukhia A
FAU - Nadkarni, Janhavi
AU  - Nadkarni J
FAU - Willis, Gareth R
AU  - Willis GR
FAU - Reis, Monica
AU  - Reis M
FAU - Zhumka, Kristjan
AU  - Zhumka K
FAU - Vitali, Sally
AU  - Vitali S
FAU - Liu, Xianlan
AU  - Liu X
FAU - Galls, Alexandra
AU  - Galls A
FAU - Mitsialis, S Alex
AU  - Mitsialis SA
FAU - Kourembanas, Stella
AU  - Kourembanas S
LA  - eng
PT  - Preprint
DEP - 20230802
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10418169
EDAT- 2023/08/14 06:42
MHDA- 2023/08/14 06:43
PMCR- 2023/08/11
CRDT- 2023/08/14 05:02
PHST- 2023/08/14 06:43 [medline]
PHST- 2023/08/14 06:42 [pubmed]
PHST- 2023/08/14 05:02 [entrez]
PHST- 2023/08/11 00:00 [pmc-release]
AID - 2023.07.31.551394 [pii]
AID - 10.1101/2023.07.31.551394 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Aug 2:2023.07.31.551394. doi: 10.1101/2023.07.31.551394.