Science - USA (2021-12-24)

INSIGHTS | PERSPECTIVES

GRAPHIC: KELLIE HOLOSKI/

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as pulmonary, vaginal, and
gastrointestinal inflamma-
tion ( 4 , 5 ), which suggests
that fibrin can accumulate
in multiple organs and
damage mucosal tissue if
not properly degraded.
Using mice expressing a
catalytically inactive form
of PLG, mice lacking the
enzymes responsible for
processing PLG to its active
form, and mice deficient
in both Plg and Fga (the
gene encoding one of the
fibrinogen chains), Silva et
al. elegantly demonstrate
that PLG prevents oral in-
flammation by specifically
preventing the accumula-
tion of fibrin. But how does
a fibrillary protein involved
in clotting trigger inflam-
mation? Silva et al. show
that fibrin deposits are
indispensable for neutro-
phil activation in the oral
mucosa. Using a combina-
tion of genetic models and
in vitro assays, the authors
demonstrate that direct en-
gagement of fibrin by the
Mac-1 receptor expressed
on neutrophils induces the
production of reactive oxy-
gen species (ROS) and neutrophil extra-
cellular traps (NETs, DNA-protein fibers),
which cause tissue damage by chemical,
lytic, or enzymatic activity. Mac-1 is ex-
pressed by all myeloid cells, and therefore
it cannot be ruled out that fibrin deposits
also convert monocytes and macrophages
into effectors of mucosal inflammation. An
important unsolved question is the identity
of the cells that locally produce fibrin de-
posits in the mucosa, because anomalous
activity from these cells—for example, that
induced by microbial dysbiosis—causes
excessive fibrin production and inflamma-
tion (see the figure).
An exciting implication from the study
of Silva et al. is that neutrophils recruited
to the site of inflammation are not by de-
fault activated and primed for tissue de-
struction. This challenges textbook neutro-
phil biology, which places recruitment as
the main, if not the exclusive, bottleneck
for overt inflammation ( 6 ). These findings
suggest that local cues strategically depos-
ited in the tissue are needed for full-blown
activation and release of the toxic arsenal
of these cells. Because the activity of neu-
trophils is generally protective against mi-
croorganisms that occasionally invade tis-

sues, the study also implies that deposits

of fibrin must be constantly produced and

degraded at the interface of the tissue and

adjacent commensal microbiota of healthy

individuals. Examination of the formation

and degradation dynamics of such proin-

flammatory fibrin hubs across tissues may

unearth mechanisms that keep inflamma-

tion in check. Neutrophils can be detected

in most naïve tissues, including the oral

cavity ( 4 , 5 ), where they acquire distinct

properties ( 7 ). It is therefore conceivable

that not only the formation of these de-

posits, but also the presence of neutrophil

populations with exaggerated responses to

fibrin, underlie pathological inflammation

of the mucosa.

Recent studies have shown that fibrin is

a key structural element of innate immu-

nity in serosal cavities in the body, where

it participates in pathogen removal and

tissue repair by trapping bacteria together

with immune cells in fibrillar aggregates

( 5 , 8 , 9 ). These studies substantiate the

mechanistic (and possibly evolutionary)

connection between coagulation and the

innate immune system, a concept that

has been reinforced by the discovery of

macrophages with platelet-like behavior

in large body cavities ( 5 ).

The work of Silva et al. ex-

tends this fascinating biol-

ogy by showing that fibrin

functions as a physical

hub to launch neutrophil

responses in the oral mu-

cosa at the right place and

time and by demonstrating

that resolving inflamma-

tion demands the removal

of these proinflammatory

substrates.

These findings raise ad-

ditional questions regard-

ing the actual mechanisms

of injury. For example,

NETs are well-established

drivers of vascular disease

through either enzymatic

or cytolytic activity ( 10 ).

However, the mechanisms

by which these DNA scaf-

folds cause bone erosion

are unclear: They could

mediate direct degradation

of the bone or indirectly

activate osteoclasts (bone-

degrading cells). This could

occur by the degradation

of proteins that prevent

bone loss ( 11 ) by the pro-

teases that decorate the

NET. Direct evidence that

immune-regulatory fibrin

substrates form in other mucosal surfaces

(such as the gut, skin, or vagina), or the

possible existence of analogous hubs in-

volving different structural proteins in

other tissues, warrants further research.

Developing therapies that exploit the

fibrin-neutrophil axis may provide much-

needed relief to those living with mucosal

inflammation. j

REFERENCES AND NOTES

1. G. Hajishengallis, Nat. Rev. Immunol. 15 , 30 (2015).


2. L. M. Silva et al., Science 374 , 1575 (2021).


3. D. W. Williams et al., Cell 184 , 4090 (2021).


4. J. W. Chadwick et al., J. Leukoc. Biol. 110 , 187 (2021).


5. J. Zindel et al., Science 371 , eabe0595 (2021).


6. S. Nourshargh, R. Alon, Immunity 41 , 694 (2014).


7. I. Ballesteros et al., Cell 183 , 1282 (2020).


8. A. Vega-Pérez et al., Immunity 54 , 2578 (2021).


9. N. Zhang et al., J. Exp. Med. 216 , 1291 (2019).


10. C. Silvestre-Roig et al., Nature 569 , 236 (2019).


11. J. Shin et al., Sci. Transl. Med. 7 , 307ra155 (2015).

ACKNOWLEDGMENTS

A.H. is a paid consultant for Flagship Pioneering. T.V. is

supported by a fellowship from the La Caixa Foundation

(ID100010434). A.H. is supported by RTI2018-095497-

B-I00 from Ministerio de Ciencia e Innovación (MICINN),

HR17_00527 from Fundación La Caixa, the Transatlantic

Network of Excellence (TNE-18CVD04) from the Leducq

Foundation, and FET-OPEN (no. 861878) from the European

Commission.

10.1126/science.abn 0399

Homeostasis Pathogenic (periodontitis)

BoneBone

Gingiva

Polymorphonuclear

leukocytes

Polymorphonuclear

leukocytes

Blood

vessel

Blood

vessel

Neutrophil

Fibrin

deposits

Fibrin

deposits

Oral microbiota

To o t h

ROS

NET

Fibrin

Bone

destruction

Bone

destruction

Inflammation of the oral mucosa

Under homeostatic conditions, microbiota may

induce the deposition of fibrin. This stimulates

the activation of neutrophils, which release toxic

reactive oxygen species (ROS) and neutrophil

extracellular traps (NETs). Degradation of fibrin

deposits by plasmin (from plasminogen) is required

to prevent excessive immune activation, chronic

inflammation, and bone destruction, which occur

during periodontitis.

1560 24 DECEMBER 2021 • VOL 374 ISSUE 6575