PMID- 36916933
OWN - NLM
STAT- MEDLINE
DCOM- 20230420
LR  - 20230915
IS  - 1098-5522 (Electronic)
IS  - 0019-9567 (Print)
IS  - 0019-9567 (Linking)
VI  - 91
IP  - 4
DP  - 2023 Apr 18
TI  - The Dual Benefit of Sulfasalazine on Pneumocystis Pneumonia-Related 
      Immunopathogenesis and Antifungal Host Defense Does Not Require IL-4Ralpha-Dependent 
      Macrophage Polarization.
PG  - e0049022
LID - 10.1128/iai.00490-22 [doi]
LID - e00490-22
AB  - Pneumocystis is a respiratory fungal pathogen that is among the most frequent 
      causes of life-threatening pneumonia (PcP) in immunocompromised hosts. Alveolar 
      macrophages play an important role in host defense against Pneumocystis, and 
      several studies have suggested that M2 polarized macrophages have 
      anti-Pneumocystis effector activity. Our prior work found that the 
      immunomodulatory drug sulfasalazine (SSZ) provides a dual benefit during 
      PcP-related immune reconstitution inflammatory syndrome (IRIS) by concurrently 
      suppressing immunopathogenesis while also accelerating macrophage-mediated fungal 
      clearance. The benefits of SSZ were associated with heightened Th2 cytokine 
      production and M2 macrophage polarization. Therefore, to determine whether SSZ 
      improves the outcome of PcP through a mechanism that requires Th2-dependent M2 
      polarization, RAG2(-/-) mice lacking interleukin 4 receptor alpha chain (IL-4Ralpha) 
      on macrophage lineage cells were generated. As expected, SSZ treatment 
      dramatically reduced the severity of PcP-related immunopathogenesis and 
      accelerated fungal clearance in immune-reconstituted RAG2(-/-) mice. Similarly, 
      SSZ treatment was also highly effective in immune-reconstituted RAG2/IL-4Ralpha(-/-) 
      and RAG2/gamma interferon receptor (IFN-gammaR)(-/-) mice, demonstrating that neither 
      IL-4Ralpha-dependent M2 nor IFN-gammaR-dependent M1 macrophage polarization programs were 
      required for the beneficial effects of SSZ. Despite the fact that macrophages 
      from RAG2/IL-4Ralpha(-/-) mice could not respond to the Th2 cytokines IL-4 and IL-13, 
      M2-biased alveolar macrophages were identified in the lungs following SSZ 
      treatment. These data demonstrate that not only does SSZ enhance phagocytosis and 
      fungal clearance in the absence of macrophage IL-4Ralpha signaling, but also that SSZ 
      promotes M2 macrophage polarization in an IL-4Ralpha-independent manner. These 
      findings could have implications for the treatment of PcP and other diseases in 
      which M2 polarization is beneficial.
FAU - Zhang, Zhuo-Qian
AU  - Zhang ZQ
AD  - Department of Microbiology and Immunology, University of Rochester School of 
      Medicine and Dentistry, Rochester, New York, USA.
FAU - Gigliotti, Francis
AU  - Gigliotti F
AD  - Department of Microbiology and Immunology, University of Rochester School of 
      Medicine and Dentistry, Rochester, New York, USA.
AD  - Department of Pediatrics, University of Rochester School of Medicine and 
      Dentistry, Rochester, New York, USA.
FAU - Wright, Terry W
AU  - Wright TW
AUID- ORCID: 0000-0001-6531-2214
AD  - Department of Microbiology and Immunology, University of Rochester School of 
      Medicine and Dentistry, Rochester, New York, USA.
AD  - Department of Pediatrics, University of Rochester School of Medicine and 
      Dentistry, Rochester, New York, USA.
LA  - eng
GR  - R01 AI117288/AI/NIAID NIH HHS/United States
GR  - R01 AI146035/AI/NIAID NIH HHS/United States
GR  - R01 HL113495/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20230314
PL  - United States
TA  - Infect Immun
JT  - Infection and immunity
JID - 0246127
RN  - 3XC8GUZ6CB (Sulfasalazine)
RN  - 0 (Antifungal Agents)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Sulfasalazine/pharmacology
MH  - *Pneumonia, Pneumocystis/drug therapy
MH  - Antifungal Agents/pharmacology
MH  - Macrophages
MH  - Macrophages, Alveolar/microbiology
MH  - *Pneumocystis
PMC - PMC10112227
OTO - NOTNLM
OT  - Pneumocystis
OT  - antifungal agents
OT  - immunopathogenesis
OT  - macrophages
OT  - opportunistic fungi
OT  - pulmonary function
OT  - sulfasalazine
COIS- The authors declare no conflict of interest.
EDAT- 2023/03/15 06:00
MHDA- 2023/04/20 06:42
PMCR- 2023/09/14
CRDT- 2023/03/14 10:06
PHST- 2023/04/20 06:42 [medline]
PHST- 2023/03/15 06:00 [pubmed]
PHST- 2023/03/14 10:06 [entrez]
PHST- 2023/09/14 00:00 [pmc-release]
AID - 00490-22 [pii]
AID - iai.00490-22 [pii]
AID - 10.1128/iai.00490-22 [doi]
PST - ppublish
SO  - Infect Immun. 2023 Apr 18;91(4):e0049022. doi: 10.1128/iai.00490-22. Epub 2023 
      Mar 14.