The role of the inflammasome in the development of aseptic inflammation in miscarriage



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Abstract

Innate immunity plays a key role in the processes of onset and maintenance of physiological pregnancy. Changes in the function of the immune system can lead to disruptions in the normal course of pregnancy and miscarriage. In recent years, the function of NOD-like receptors (NLR) of innate immunity in pregnancy pathologies has been actively studied. NLRs are intracellular receptors that recognize a wide range of ligands and participate in various mechanisms, including the assembly of the inflammasome. The inflammasome is a cytoplasmic high-molecular-weight protein complex that initiates inflammation in response to infection or endogenous signals of cellular stress and tissue damage. The expression of genes, as well as the protein products of NLRP3 inflammasome activation, are found at different levels of the female reproductive tract, including placenta and fetal membranes. Increasing evidence supports a role for NLRP3 inflammasome in the development of reproductive abnormalities, including infertility and miscarriage. Inflammasome activity is conditioned by a large number of endogenous factors, disruption of any of which can lead to the development of aseptic inflammation. The outcome of such inflammation is often spontaneous miscarriage and preterm labor. NLRP3 inflammasome activation can be caused by disorders in which the concentration of molecules stimulating the NLRP3 receptor is increased at the systemic or local level. The study of the established non-infectious factors of NLRP3 overactivation and introduction of their diagnostics into clinical practice will allow timely detection and reduction risks associated with pregnancy loss.

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Picture 1

(a) Structure of the NLR receptor: The NLR contains 3 domains with different functions. C-terminal domain rich in leucine-rich repeats (LRR) is involved in ligand recognition; NACHT domain - binding and oligomerization domain is located in the central part of the molecule; N-terminal domain is involved in protein-protein interactions and differs from one NLR to another. (c) Depending on the structure of the N-terminal domain, 4 NLR subfamilies are distinguished: NLRP (containing the pyrin domain PYD), NLRC (containing the caspase activation and recruitment domain CARD), NLRA (containing the acidic transactivating domain, AD), NLRB (containing baculovirus repeats of apoptosis inhibitors, BIR). (b) NLR family proteins are involved in functionally distinct processes: intracellular signal transduction, transcription activation, autophagy, and inflammasome assembly. (b, c) NLRs such as NLRP1, NLRP2, NLRP3, NLRC4 are involved in inflammasome assembly.

Picture 2

1) Inflammasome activation is preceded by a priming step, which requires TLR stimulation followed by NF-κB activation. NF-κB increases gene expression of key inflammatory proteins: NLR3, ASC, Pro-CASP-1, pro-IL-1β.

2) NLRP3 is located intracellularly and participates in ligand recognition; its stimulation leads to the assembly of the inflammasome with the attachment of the adapter protein ASC and procaspase-1 (Pro-CASP1) to NLRP3. Subsequently, Pro-CASP1 is activated to form CASP1, which is involved in the formation of active forms of proinflammatory cytokines (IL-1β) and gazdermin-D (GSDMD). In turn, GSDMD promotes the formation of pores in the plasma membrane, which leads to cell pyroptosis and release of proinflammatory cytokines into the extracellular medium.

3) Inflammasome activation is provided by a wide range of stimuli (circled in red in the figure): mitochondrial dysfunction with the release of ROS (reactive oxygen species), DNA; changes in the ionic composition of the cytoplasm (outflow of K+, release of Ca2+ from the endoplasmic reticulum); damage to lysosomes with the release of cathepsin after their uptake of crystalline molecules; PAMP, DAMP.

Picture 3

1) Pathologic activation of NLRP3 inflammasome in endometrial tissues impairs endometrial receptivity and fetal egg attachment, which clinically may manifest as infertility or early miscarriage.

2) NLRP3-induced inflammation at the mother-fetus interface promotes increased prostaglandin (PG) levels and oxytocin receptor stimulation, which promotes myometrial contractile activity and cervical opening. The activation of these mechanisms results in the rejection of the fetal egg and pregnancy loss (spontaneous miscarriage or premature labor).

3) Non-infectious factors contributing to excessive activation of NLRP3 inflammasome may be diabetes mellitus, obesity, hyperuricemia, genetic disorders, antiphospholipid syndrome.

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About the authors

Polina I. Kukina

I.I. Mechnikov FGBNU NIIVS. Moscow, Russia

Author for correspondence.
Email: renoru47@gmail.com
ORCID iD: 0000-0002-0054-6754
SPIN-code: 7021-6761
Russian Federation

Yulia E. Dobrokhotova

N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia

Email: pr.dobrohotova@mail.ru
ORCID iD: 0000-0002-7830-2290

Dr. Med. Sci., Professor, Head of the Department of Obstetrics and Gynecology, Faculty of Medicine

Russian Federation, Moscow

Eleonora A. Markova

Pirogov Russian National Research Medical University

Email: markova.eleonora@mail.ru
ORCID iD: 0000-0002-9491-9303

Cand. Sci. (Med.)

Russian Federation, Moscow

Ksenia A. Makhortova

Email: makhortovakseniy20@mail.ru
ORCID iD: 0009-0007-1459-3854

Oksana A. Svitich

Mechnikov Research Institute of Vaccines and Sera; I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: svitichoa@yandex.ru
ORCID iD: 0000-0003-1757-8389
SPIN-code: 8802-5569

MD, Dr. Sci. (Medicine), Professor, Corresponding Member of the Russian Academy of Sciences

Moscow; Moscow

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